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1. Increased Susceptibility to Pilocarpine-Induced Status Epilepticus and Reduced Latency in TRPC1/4 Double Knockout Mice

Author

Fang Zheng, Kevin D. Phelan, and U Thaung Shwe

Subjects
TRPC channels, EEG, status epilepticus, Medicine, Internal medicine, RC31-1245, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Canonical transient receptor potential channels (TRPCs) are a family of calcium-permeable cation channels. Previous studies have shown that heteromeric channels comprising TRPC1 and TRPC4 mediate epileptiform bursting in lateral septal neurons and hippocampal CA1 pyramidal neurons, suggesting that TRPC1/4 channels play a pro-seizure role. In this study, we utilized electroencephalography (EEG) recording and spectral analysis to assess the role of TRPC1/4 channels in the pilocarpine model of status epilepticus (SE). We found that, surprisingly, TRPC1/4 double knockout (DKO) mice exhibited an increased susceptibility to pilocarpine-induced SE. Furthermore, SE latency was also significantly reduced in TRPC1/4 DKO mice. Further studies are needed to reveal the underlying mechanisms of our unexpected results.

Published
2023
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2. MC4R Localizes at Excitatory Postsynaptic and Peri-Postsynaptic Sites of Hypothalamic Neurons in Primary Culture

Author

Haven Griffin, Jude Hanson, Kevin D. Phelan, and Giulia Baldini

Subjects
MC4R, postsynaptic sites, GPCR, hypothalamic neuron, primary culture, NMDAR, Cytology, QH573-671
Abstract

The melanocortin-4 receptor (MC4R) is a G protein-coupled receptor (GPCR) that is expressed in several brain locations encompassing the hypothalamus and the brainstem, where the receptor controls several body functions, including metabolism. In a well-defined pathway to decrease appetite, hypothalamic proopiomelanocortin (POMC) neurons localized in the arcuate nucleus (Arc) project to MC4R neurons in the paraventricular nuclei (PVN) to release the natural MC4R agonist α-melanocyte-stimulating hormone (α-MSH). Arc neurons also project excitatory glutamatergic fibers to the MC4R neurons in the PVN for a fast synaptic transmission to regulate a satiety pathway potentiated by α-MSH. By using super-resolution microscopy, we found that in hypothalamic neurons in a primary culture, postsynaptic density protein 95 (PSD95) colocalizes with GluN1, a subunit of the ionotropic N-methyl-D-aspartate receptor (NMDAR). Thus, hypothalamic neurons form excitatory postsynaptic specializations. To study the MC4R distribution at these sites, tagged HA-MC4R under the synapsin promoter was expressed in neurons by adeno-associated virus (AAV) gene transduction. HA-MC4R immunofluorescence peaked at the center and in proximity to the PSD95- and NMDAR-expressing sites. These data provide morphological evidence that MC4R localizes together with glutamate receptors at postsynaptic and peri-postsynaptic sites.

Published
2024
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3. Investigating Contributions of Canonical Transient Receptor Potential Channel 3 to Hippocampal Hyperexcitability and Seizure-Induced Neuronal Cell Death

Author

Kevin D. Phelan, U Thaung Shwe, Hong Wu, and Fang Zheng

Subjects
resting membrane potential, cell resistance, excitability, paired-pulse facilitation, FluoroJade staining, stereology, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract

Canonical transient receptor potential channel 3 (TRPC3) is the most abundant TRPC channel in the brain and is highly expressed in all subfields of the hippocampus. Previous studies have suggested that TRPC3 channels may be involved in the hyperexcitability of hippocampal pyramidal neurons and seizures. Genetic ablation of TRPC3 channel expression reduced the intensity of pilocarpine-induced status epilepticus (SE). However, the underlying cellular mechanisms remain unexplored and the contribution of TRPC3 channels to SE-induced neurodegeneration is not determined. In this study, we investigated the contribution of TRPC3 channels to the electrophysiological properties of hippocampal pyramidal neurons and hippocampal synaptic plasticity, and the contribution of TRPC3 channels to seizure-induced neuronal cell death. We found that genetic ablation of TRPC3 expression did not alter basic electrophysiological properties of hippocampal pyramidal neurons and had a complex impact on epileptiform bursting in CA3. However, TRPC3 channels contribute significantly to long-term potentiation in CA1 and SE-induced neurodegeneration. Our results provided further support for therapeutic potential of TRPC3 inhibitors and raised new questions that need to be answered by future studies.

Published
2024
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4. Oncogenic RAS commandeers amino acid sensing machinery to aberrantly activate mTORC1 in multiple myeloma

Author

Yandan Yang, Arnold Bolomsky, Thomas Oellerich, Ping Chen, Michele Ceribelli, Björn Häupl, George W. Wright, James D. Phelan, Da Wei Huang, James W. Lord, Callie K. Van Winkle, Xin Yu, Jan Wisniewski, James Q. Wang, Frances A. Tosto, Erin Beck, Kelli Wilson, Crystal McKnight, Jameson Travers, Carleen Klumpp-Thomas, Grace A. Smith, Stefania Pittaluga, Irina Maric, Dickran Kazandjian, Craig J. Thomas, and Ryan M. Young

Subjects
Science
Abstract

RAS mutations are commonly found in multiple myeloma (MM). Here, the authors show that oncogenic RAS mutations activate mTORC1 signalling in MM and combining mTORC1 and MEK/ERK inhibitors synergize to improve survival in preclinical models.

Published
2022
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5. Bootstrapped Dimensional Crossover of a Spin Density Wave

Author

Anjana M. Samarakoon, J. Strempfer, Junjie Zhang, Feng Ye, Yiming Qiu, J.-W. Kim, H. Zheng, S. Rosenkranz, M. R. Norman, J. F. Mitchell, and D. Phelan

Subjects
Physics, QC1-999
Abstract

Quantum materials display rich and myriad types of magnetic, electronic, and structural ordering, often with these ordering modes either competing with one another or “intertwining,” that is, reinforcing one another. Low-dimensional quantum materials influenced strongly by competing interactions and/or geometric frustration are particularly susceptible to such ordering phenomena and thus offer fertile ground for understanding the consequent emergent collective quantum phenomena. Such is the case of the quasi-2D materials R_{4}Ni_{3}O_{10} (R=La, Pr), in which intertwined charge- and spin-density waves (CDW and SDW) on the Ni sublattice have been identified and characterized. Not unexpectedly, these density waves are largely quasi-2D as a result of weak coupling between planes, compounded with magnetic frustration. In the case of R=Pr, however, we show here that exchange coupling between the transition-metal and rare-earth sublattices upon cooling overcomes both obstacles, leading to a dimensional crossover into a fully 3D-ordered and coupled SDW state on both sublattices, as an induced moment on notionally nonmagnetic Pr^{3+} opens exchange pathways in the third dimension. In the process, the structure of the SDW on the Ni sublattice is irreversibly altered, an effect that survives reheating of the material until the underlying CDW melts. This “bootstrapping” mechanism linking incommensurate SDWs on the two sublattices illustrates a new member of the multitude of quantum states that low-dimensional magnets can express, driven by coupled orders and modulated by frustrated exchange pathways.

Published
2023
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6. Pharmacological Differences between Native Homomeric Transient Receptor Potential Canonical Type 4 Channels and Heteromeric Transient Receptor Potential Canonical Type 1/4 Channels in Lateral Septal Neurons

Author

Kevin D. Phelan, U Thaung Shwe, and Fang Zheng

Subjects
TRPC, epileptiform bursting, mGluRs, ML204, La3+, Medicine, Pharmacy and materia medica, RS1-441
Abstract

Given the unique expression patterns and revelations of its critical involvement in a host of neurological disorders, the TRPC1/4/5 subgroup has become an intense target of drug development, and some compounds are now in clinical trials. However, little is known about the exact subunit composition of this subfamily of TRPC channels in various native tissues, and whether it has functional and pharmacological implications. In this study, we investigated the effects of two TRPC4 modulators located in the lateral septum, in which a metabotropic glutamate receptor (mGluR) agonist-induced plateau potential is mediated by TRPC channels composed of TRPC1 and TRPC4. Lateral septal neurons were recorded intracellularly in brain slices using sharp electrodes. Drugs were applied via bath superfusion. We showed that the plateau potential in mice lacking TRPC1 is modulated by ML204 and La3+ in a manner that is like homomeric TRPC4 channels in artificial expression systems. However, the plateau potential that is primarily mediated by heteromeric TRPC1/4 channels in lateral septal neurons in wildtype mice was modulated differently by ML204 and La3+. Our data suggest that native homomeric TRPC4 channels and heteromeric TRPC1/4 channels are pharmacologically distinct, and the current drug development strategy regarding TRPC1/4/5 may need to be reevaluated.

Published
2023
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7. In vivo CRISPR screens reveal a HIF-1α-mTOR-network regulates T follicular helper versus Th1 cells

Author

Bonnie Huang, James D. Phelan, Silvia Preite, Julio Gomez-Rodriguez, Kristoffer H. Johansen, Hirofumi Shibata, Arthur L. Shaffer, Qin Xu, Brendan Jeffrey, Martha Kirby, Stacie Anderson, Yandan Yang, Selamawit Gossa, Dorian B. McGavern, Louis M. Staudt, and Pamela L. Schwartzberg

Subjects
Science
Abstract

T follicular helper (Tfh) and T help type 1 (Th1) cells both arise from naïve CD4 T cells, but detailed knowledge of their differentiation remains incomplete. Here the authors pursue an in vivo CRISPR screen to identify genes, focusing on druggable targets, regulating Tfh versus Th1 to provide a resource for related studies, while also implicating HIF-1α and VHL in this regulation.

Published
2022
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8. Intertwined density waves in a metallic nickelate

Author

Junjie Zhang, D. Phelan, A. S. Botana, Yu-Sheng Chen, Hong Zheng, M. Krogstad, Suyin Grass Wang, Yiming Qiu, J. A. Rodriguez-Rivera, R. Osborn, S. Rosenkranz, M. R. Norman, and J. F. Mitchell

Subjects
Science
Abstract

Layered Ruddlesden-Popper structure nickelates R 4Ni3O10 (R = La,Pr) show an unusual metal-to-metal transition, but its origin has remained elusive for more than two decades. Here, the authors show that this transition results from intertwined density waves that arise from a coupling between charge and spin degrees of freedom

Published
2020
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9. Liraglutide Counteracts Endoplasmic Reticulum Stress in Palmitate-Treated Hypothalamic Neurons without Restoring Mitochondrial Homeostasis

Author

Haven Griffin, Sarah C. Sullivan, Steven W. Barger, Kevin D. Phelan, and Giulia Baldini

Subjects
endoplasmic reticulum, palmitate, obesity, liraglutide, metformin, mitochondria, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract

One feature of high-fat diet-induced neurodegeneration in the hypothalamus is an increased level of palmitate, which is associated with endoplasmic reticulum (ER) stress, loss of CoxIV, mitochondrial fragmentation, and decreased abundance of MC4R. To determine whether antidiabetic drugs protect against ER and/or mitochondrial dysfunction by lipid stress, hypothalamic neurons derived from pre-adult mice and neuronal Neuro2A cells were exposed to elevated palmitate. In the hypothalamic neurons, palmitate exposure increased expression of ER resident proteins, including that of SERCA2, indicating ER stress. Liraglutide reverted such altered ER proteostasis, while metformin only normalized SERCA2 expression. In Neuro2A cells liraglutide, but not metformin, also blunted dilation of the ER induced by palmitate treatment, and enhanced abundance and expression of MC4R at the cell surface. Thus, liraglutide counteracts, more effectively than metformin, altered ER proteostasis, morphology, and folding capacity in neurons exposed to fat. In palmitate-treated hypothalamic neurons, mitochondrial fragmentation took place together with loss of CoxIV and decreased mitochondrial membrane potential (MMP). Metformin, but not liraglutide, reverted mitochondrial fragmentation, and both liraglutide and metformin did not protect against either loss of CoxIV abundance or MMP. Thus, ER recovery from lipid stress can take place in hypothalamic neurons in the absence of recovered mitochondrial homeostasis.

Published
2022
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10. Publisher Correction: Oncogenic RAS commandeers amino acid sensing machinery to aberrantly activate mTORC1 in multiple myeloma

Author

Yandan Yang, Arnold Bolomsky, Thomas Oellerich, Ping Chen, Michele Ceribelli, Björn Häupl, George W. Wright, James D. Phelan, Da Wei Huang, James W. Lord, Callie K. Van Winkle, Xin Yu, Jan Wisniewski, James Q. Wang, Frances A. Tosto, Erin Beck, Kelli Wilson, Crystal McKnight, Jameson Travers, Carleen Klumpp-Thomas, Grace A. Smith, Stefania Pittaluga, Irina Maric, Dickran Kazandjian, Craig J. Thomas, and Ryan M. Young

Subjects
Science
Published
2022
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11. Selective Survival of Sim1/MC4R Neurons in Diet-Induced Obesity

Author

Eugene Nyamugenda, Haven Griffin, Susan Russell, Kimberly A. Cooney, Nicholas S. Kowalczyk, Ishrar Islam, Kevin D. Phelan, and Giulia Baldini

Subjects
biological sciences, human physiology, and molecular neuroscience, Science
Abstract

Summary: In the melanocortin pathway, melanocortin-4 receptor (MC4R) functions to control energy homeostasis. MC4R is expressed in a sub-population of Sim1 neurons (Sim1/MC4R neurons) and functions in hypothalamic paraventricular nuclei (PVN) to control food intake. Mapping sites of hypothalamic injury in obesity is essential to counteract the disease. In the PVN of male and female mice with diet-induced obesity (DIO) there is neuronal loss. However, the existing subpopulation of PVN Sim1/MC4R neurons is unchanged, but has a loss of mitochondria and MC4R protein. In mice of both sexes with DIO, dietary intervention to re-establish normal weight restores abundance of MC4R protein in Sim1/MC4R neurons and neurogenesis in the PVN. However, the number of non-Sim1/MC4R neurons in the PVN continues to remain decreased. Selective survival and recovery of Sim1/MC4R neurons after DIO suggests these neurons as preferential target to restore energy homeostasis and of therapy against obesity.

Published
2020
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12. Targeting N-linked Glycosylation for the Therapy of Aggressive Lymphomas

Author

Sebastian Scheich, Jiji Chen, Jiamin Liu, Frank Schnutgen, Julius C. Enssle, Michele Ceribelli, Craig J. Thomas, Jaewoo Choi, Vivian Morris, Tony Hsiao, Hang Nguyen, Boya Wang, Arnold Bolomsky, James D. Phelan, Sean Corcoran, Henning Urlaub, Ryan M. Young, Bjorn Haupl, George W. Wright, Da Wei Huang, Yanlong Ji, Xin Yu, Weihong Xu, Yandan Yang, Hong Zhao, Jagan Muppidi, Kuan-Ting Pan, Thomas Oellerich, and Louis M. Staudt

Subjects
Oncology
Abstract

Diffuse large B-cell lymphoma (DLBCL) can be subdivided into activated B-cell like (ABC) and germinal center B-cell-like (GCB) DLCBL. Self-antigen engagement of B-cell receptors (BCRs) in ABC tumors induces their clustering, thereby initiating chronic active signaling and activation of NF-kB and PI3 kinase. Constitutive BCR signaling is essential in some GCB tumors but primarily activates PI3 kinase. We devised genome-wide CRISPR-Cas9 screens to identify regulators of IRF4, a direct transcriptional target of NF-kB and an indicator of proximal BCR signaling in ABC DLBCL. Unexpectedly, inactivation of N-linked protein glycosylation by the oligosaccharyltransferase-B (OST-B) complex reduced IRF4 expression. OST-B inhibition of BCR glycosylation reduced BCR clustering and internalization while promoting its association with CD22, which attenuated PI3 kinase and NF-kB activation. By directly interfering with proximal BCR signaling, OST-B inactivation killed models of ABC and GCB DLBCL, supporting the development of selective OST-B inhibitors for the treatment of these aggressive cancers.

Published
2023

13. Supplementary Table 7 from Overcoming Acquired Epigenetic Resistance to BTK Inhibitors

Author

Louis M. Staudt, Adrian Wiestner, Wyndham H. Wilson, Erika M. Gaglione, Clare Sun, Inhye E. Ahn, Michael C. Kelly, Zachary Rae, Thomas Oellerich, Björn Häupl, Craig J. Thomas, Carleen Klumpp-Thomas, Crystal McKnight, Lu Chen, Kelli M. Wilson, Xiaohu Zhang, Michele Ceribelli, Sandrine Roulland, Weihong Xu, Xin Yu, Hong Zhao, Yandan Yang, Daniel E. Webster, Ryan M. Young, Jaewoo Choi, Monica Kasbekar, George W. Wright, DaWei Huang, James Q. Wang, James D. Phelan, and Arthur L. Shaffer

Abstract

Supplemental Table 7. Targeting epigenetic resistance to BTK inhibitor treatment in ABC DLBCL, relates to Fig7

Published
2023

14. Supplementary Table 1 from Overcoming Acquired Epigenetic Resistance to BTK Inhibitors

Author

Louis M. Staudt, Adrian Wiestner, Wyndham H. Wilson, Erika M. Gaglione, Clare Sun, Inhye E. Ahn, Michael C. Kelly, Zachary Rae, Thomas Oellerich, Björn Häupl, Craig J. Thomas, Carleen Klumpp-Thomas, Crystal McKnight, Lu Chen, Kelli M. Wilson, Xiaohu Zhang, Michele Ceribelli, Sandrine Roulland, Weihong Xu, Xin Yu, Hong Zhao, Yandan Yang, Daniel E. Webster, Ryan M. Young, Jaewoo Choi, Monica Kasbekar, George W. Wright, DaWei Huang, James Q. Wang, James D. Phelan, and Arthur L. Shaffer

Abstract

Supplemental Table 1. Epigenetic Ibrutinib Resistance in ABC DLBCL lines, , relates to Fig. 1

Published
2023

15. Supplementary Figures and Legends from Overcoming Acquired Epigenetic Resistance to BTK Inhibitors

Author

Louis M. Staudt, Adrian Wiestner, Wyndham H. Wilson, Erika M. Gaglione, Clare Sun, Inhye E. Ahn, Michael C. Kelly, Zachary Rae, Thomas Oellerich, Björn Häupl, Craig J. Thomas, Carleen Klumpp-Thomas, Crystal McKnight, Lu Chen, Kelli M. Wilson, Xiaohu Zhang, Michele Ceribelli, Sandrine Roulland, Weihong Xu, Xin Yu, Hong Zhao, Yandan Yang, Daniel E. Webster, Ryan M. Young, Jaewoo Choi, Monica Kasbekar, George W. Wright, DaWei Huang, James Q. Wang, James D. Phelan, and Arthur L. Shaffer

Abstract

Supplemental Information- Figures & Legends (Supplemental Tables loaded separately)

Published
2023

16. Supplementary Table 6 from Overcoming Acquired Epigenetic Resistance to BTK Inhibitors

Author

Louis M. Staudt, Adrian Wiestner, Wyndham H. Wilson, Erika M. Gaglione, Clare Sun, Inhye E. Ahn, Michael C. Kelly, Zachary Rae, Thomas Oellerich, Björn Häupl, Craig J. Thomas, Carleen Klumpp-Thomas, Crystal McKnight, Lu Chen, Kelli M. Wilson, Xiaohu Zhang, Michele Ceribelli, Sandrine Roulland, Weihong Xu, Xin Yu, Hong Zhao, Yandan Yang, Daniel E. Webster, Ryan M. Young, Jaewoo Choi, Monica Kasbekar, George W. Wright, DaWei Huang, James Q. Wang, James D. Phelan, and Arthur L. Shaffer

Abstract

Supplemental Table 6. RAC2 protein interactions are a marker of epigenetic ibrutinib resistance

Published
2023

17. Supplementary Table 4 from Overcoming Acquired Epigenetic Resistance to BTK Inhibitors

Author

Louis M. Staudt, Adrian Wiestner, Wyndham H. Wilson, Erika M. Gaglione, Clare Sun, Inhye E. Ahn, Michael C. Kelly, Zachary Rae, Thomas Oellerich, Björn Häupl, Craig J. Thomas, Carleen Klumpp-Thomas, Crystal McKnight, Lu Chen, Kelli M. Wilson, Xiaohu Zhang, Michele Ceribelli, Sandrine Roulland, Weihong Xu, Xin Yu, Hong Zhao, Yandan Yang, Daniel E. Webster, Ryan M. Young, Jaewoo Choi, Monica Kasbekar, George W. Wright, DaWei Huang, James Q. Wang, James D. Phelan, and Arthur L. Shaffer

Abstract

Supplemental Table 4. Altered dependencies in ibrutinib resistant ABC DLBCL, relates to Fig. 4

Published
2023

18. Supplementary Methods from Overcoming Acquired Epigenetic Resistance to BTK Inhibitors

Author

Louis M. Staudt, Adrian Wiestner, Wyndham H. Wilson, Erika M. Gaglione, Clare Sun, Inhye E. Ahn, Michael C. Kelly, Zachary Rae, Thomas Oellerich, Björn Häupl, Craig J. Thomas, Carleen Klumpp-Thomas, Crystal McKnight, Lu Chen, Kelli M. Wilson, Xiaohu Zhang, Michele Ceribelli, Sandrine Roulland, Weihong Xu, Xin Yu, Hong Zhao, Yandan Yang, Daniel E. Webster, Ryan M. Young, Jaewoo Choi, Monica Kasbekar, George W. Wright, DaWei Huang, James Q. Wang, James D. Phelan, and Arthur L. Shaffer

Abstract

Supplementary Methods

Published
2023

19. Supplementary Table 2 from Overcoming Acquired Epigenetic Resistance to BTK Inhibitors

Author

Louis M. Staudt, Adrian Wiestner, Wyndham H. Wilson, Erika M. Gaglione, Clare Sun, Inhye E. Ahn, Michael C. Kelly, Zachary Rae, Thomas Oellerich, Björn Häupl, Craig J. Thomas, Carleen Klumpp-Thomas, Crystal McKnight, Lu Chen, Kelli M. Wilson, Xiaohu Zhang, Michele Ceribelli, Sandrine Roulland, Weihong Xu, Xin Yu, Hong Zhao, Yandan Yang, Daniel E. Webster, Ryan M. Young, Jaewoo Choi, Monica Kasbekar, George W. Wright, DaWei Huang, James Q. Wang, James D. Phelan, and Arthur L. Shaffer

Abstract

Supplemental Table2. Tracking the evolution of ibrutinib resistance phenotypes, relates to Fig. 2

Published
2023

20. Oligos and Primers - related to Methods from Overcoming Acquired Epigenetic Resistance to BTK Inhibitors

Author

Louis M. Staudt, Adrian Wiestner, Wyndham H. Wilson, Erika M. Gaglione, Clare Sun, Inhye E. Ahn, Michael C. Kelly, Zachary Rae, Thomas Oellerich, Björn Häupl, Craig J. Thomas, Carleen Klumpp-Thomas, Crystal McKnight, Lu Chen, Kelli M. Wilson, Xiaohu Zhang, Michele Ceribelli, Sandrine Roulland, Weihong Xu, Xin Yu, Hong Zhao, Yandan Yang, Daniel E. Webster, Ryan M. Young, Jaewoo Choi, Monica Kasbekar, George W. Wright, DaWei Huang, James Q. Wang, James D. Phelan, and Arthur L. Shaffer

Abstract

Oligo and Primer Tables

Published
2023

21. Supplementary Table 5 from Overcoming Acquired Epigenetic Resistance to BTK Inhibitors

Author

Louis M. Staudt, Adrian Wiestner, Wyndham H. Wilson, Erika M. Gaglione, Clare Sun, Inhye E. Ahn, Michael C. Kelly, Zachary Rae, Thomas Oellerich, Björn Häupl, Craig J. Thomas, Carleen Klumpp-Thomas, Crystal McKnight, Lu Chen, Kelli M. Wilson, Xiaohu Zhang, Michele Ceribelli, Sandrine Roulland, Weihong Xu, Xin Yu, Hong Zhao, Yandan Yang, Daniel E. Webster, Ryan M. Young, Jaewoo Choi, Monica Kasbekar, George W. Wright, DaWei Huang, James Q. Wang, James D. Phelan, and Arthur L. Shaffer

Abstract

Supplemental Table 5. RAC2 as a mediator of epigenetic ibrutinib resistance, , relates to Fig5

Published
2023

22. Data from Overcoming Acquired Epigenetic Resistance to BTK Inhibitors

Author

Louis M. Staudt, Adrian Wiestner, Wyndham H. Wilson, Erika M. Gaglione, Clare Sun, Inhye E. Ahn, Michael C. Kelly, Zachary Rae, Thomas Oellerich, Björn Häupl, Craig J. Thomas, Carleen Klumpp-Thomas, Crystal McKnight, Lu Chen, Kelli M. Wilson, Xiaohu Zhang, Michele Ceribelli, Sandrine Roulland, Weihong Xu, Xin Yu, Hong Zhao, Yandan Yang, Daniel E. Webster, Ryan M. Young, Jaewoo Choi, Monica Kasbekar, George W. Wright, DaWei Huang, James Q. Wang, James D. Phelan, and Arthur L. Shaffer

Abstract

The use of Bruton tyrosine kinase (BTK) inhibitors to block B-cell receptor (BCR)–dependent NF-κB activation in lymphoid malignancies has been a major clinical advance, yet acquired therapeutic resistance is a recurring problem. We modeled the development of resistance to the BTK inhibitor ibrutinib in the activated B-cell (ABC) subtype of diffuse large B-cell lymphoma, which relies on chronic active BCR signaling for survival. The primary mode of resistance was epigenetic, driven in part by the transcription factor TCF4. The resultant phenotypic shift altered BCR signaling such that the GTPase RAC2 substituted for BTK in the activation of phospholipase Cγ2, thereby sustaining NF-κB activity. The interaction of RAC2 with phospholipase Cγ2 was also increased in chronic lymphocytic leukemia cells from patients with persistent or progressive disease on BTK inhibitor treatment. We identified clinically available drugs that can treat epigenetic ibrutinib resistance, suggesting combination therapeutic strategies.Significance:In diffuse large B-cell lymphoma, we show that primary resistance to BTK inhibitors is due to epigenetic rather than genetic changes that circumvent the BTK blockade. We also observed this resistance mechanism in chronic lymphocytic leukemia, suggesting that epigenetic alterations may contribute more to BTK inhibitor resistance than currently thought.See related commentary by Pasqualucci, p. 555.This article is highlighted in the In This Issue feature, p. 549

Published
2023

23. Supplementary Table 3 from Overcoming Acquired Epigenetic Resistance to BTK Inhibitors

Author

Louis M. Staudt, Adrian Wiestner, Wyndham H. Wilson, Erika M. Gaglione, Clare Sun, Inhye E. Ahn, Michael C. Kelly, Zachary Rae, Thomas Oellerich, Björn Häupl, Craig J. Thomas, Carleen Klumpp-Thomas, Crystal McKnight, Lu Chen, Kelli M. Wilson, Xiaohu Zhang, Michele Ceribelli, Sandrine Roulland, Weihong Xu, Xin Yu, Hong Zhao, Yandan Yang, Daniel E. Webster, Ryan M. Young, Jaewoo Choi, Monica Kasbekar, George W. Wright, DaWei Huang, James Q. Wang, James D. Phelan, and Arthur L. Shaffer

Abstract

Supplemental Table 3. Epigenetic retuning of oncogenic signaling in ibrutinib resistance, relates to Fig. 3

Published
2023

24. Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, and Lenalidomide (ViPOR) in Relapsed and Refractory Follicular Lymphoma: Analysis of Safety, Efficacy, and Minimal Residual Disease

Author

Christopher Melani, Rahul Lakhotia, Stefania Pittaluga, James D. Phelan, Jillian Simard, Jagan R. Muppidi, Craig J. Thomas, Michele Ceribelli, Frances Anne Tosto, Rafic J. Farah, Seung Tae Lee, Amynah Pradhan, Anna Marie Juanitez, Seth M. Steinberg, Elaine S. Jaffe, Mark Roschewski, Louis M. Staudt, and Wyndham H. Wilson

Subjects
Immunology, Cell Biology, Hematology, Biochemistry
Published
2022

25. ESICM LIVES 2016: part one

Author

L. Bos, L. Schouten, L. van Vught, M. Wiewel, D. Ong, O. Cremer, A. Artigas, I. Martin-Loeches, A. Hoogendijk, T. van der Poll, J. Horn, N. Juffermans, M. Schultz, N. de Prost, T. Pham, G. Carteaux, A. Mekontso Dessap, C. Brun-Buisson, E. Fan, G. Bellani, J. Laffey, A. Mercat, L. Brochard, B. Maitre, LUNG SAFE investigators and the ESICM study group, P. A. Howells, D. R. Thickett, C. Knox, D. P. Park, F. Gao, O. Tucker, T. Whitehouse, D. F. McAuley, G. D. Perkins, LUNG SAFE Investigators and the ESICM Trials Group, L. Pisani, J. P. Roozeman, F. D. Simonis, A. Giangregorio, L. R. Schouten, S. M. Van der Hoeven, A. Serpa Neto, E. Festic, A. M. Dondorp, S. Grasso, L. D. Bos, M. J. Schultz, M. Koster-Brouwer, D. Verboom, B. Scicluna, K. van de Groep, J. Frencken, M. Bonten, J. I. Ko, K. S. Kim, G. J. Suh, W. Y. Kwon, K. Kim, J. H. Shin, O. T. Ranzani, E. Prina, R. Menendez, A. Ceccato, R. Mendez, C. Cilloniz, A. Gabarrus, M. Ferrer, A. Torres, A. Urbano, L. A. Zhang, D. Swigon, F. Pike, R. S. Parker, G. Clermont, C. Scheer, S. O. Kuhn, A. Modler, M. Vollmer, C. Fuchs, K. Hahnenkamp, S. Rehberg, M. Gründling, A. Taggu, N. Darang, N. Öveges, I. László, K. Tánczos, M. Németh, G. Lebák, B. Tudor, D. Érces, J. Kaszaki, W. Huber, D. Trásy, Z. Molnár, G. Ferrara, V. S. Kanoore Edul, H. S. Canales, E. Martins, C. Canullán, G. Murias, M. O. Pozo, J. F. Caminos Eguillor, M. G. Buscetti, C. Ince, A. Dubin, H. D. Aya, A. Rhodes, N. Fletcher, R. M. Grounds, M. Cecconi, M. Jacquet-Lagrèze, M. Riche, R. Schweizer, P. Portran, W. Fornier, M. Lilot, J. Neidecker, J. L. Fellahi, A. Escoresca-Ortega, A. Gutiérrez-Pizarraya, L. Charris-Castro, Y. Corcia-Palomo, E. Fernandez-Delgado, J. Garnacho-Montero, C. Roger, L. Muller, L. Elotmani, J. Lipman, J. Y. Lefrant, J. A. Roberts, R. Muñoz-Bermúdez, M. Samper, C. Climent, F. Vasco, V. Sara, S. Luque, N. Campillo, S. Grau Cerrato, J. R. Masclans, F. Alvarez-Lerma, S. Carvalho Brugger, G. Jimenez Jimenez, M. Miralbés Torner, J. Trujillano Cabello, B. Balsera Garrido, X. Nuvials Casals, F. Barcenilla Gaite, M. Vallverdú Vidal, M. Palomar Martínez, V. Gusarov, D. Shilkin, M. Dementienko, E. Nesterova, N. Lashenkova, A. Kuzovlev, M. Zamyatin, A. Demoule, S. Carreira, S. Lavault, O. Palancca, E. Morawiec, J. Mayaux, I. Arnulf, T. Similowski, B. S. Rasmussen, R. G. Maltesen, M. Hanifa, S. Pedersen, S. R. Kristensen, R. Wimmer, M. Panigada, G. Li Bassi, T. Kolobow, A. Zanella, M. Cressoni, L. Berra, V. Parrini, H. Kandil, G. Salati, S. Livigni, A. Amatu, A. Andreotti, F. Tagliaferri, G. Moise, G. Mercurio, A. Costa, A. Vezzani, S. Lindau, J. Babel, M. Cavana, D. Consonni, A. Pesenti, L. Gattinoni, for the GRAVITY-VAP TRIAL NETWORK, P. Mansouri, F. Zand, L. Zahed, F. Dehghanrad, M. Bahrani, M. Ghorbani, B. Cambiaghi, O. Moerer, T. Mauri, N. Kunze-Szikszay, C. Ritter, M. Quintel, L. M. Vilander, M. A. Kaunisto, S. T. Vaara, V. Pettilä, FINNAKI Study Group, J. L. G. Haitsma Mulier, S. Rozemeijer, A. M. E. Spoelstra-de Man, P. E. Elbers, P. R. Tuinman, M. C. de Waard, H. M. Oudemans-van Straaten, A. M. A. Liberatore, R. B. Souza, A. M. C. R. P. F. Martins, J. C. F. Vieira, I. H. J. Koh, M. Galindo Martínez, R. Jiménez Sánchez, L. Martínez Gascón, M. D. Rodríguez Mulero, A. Ortín Freire, A. Ojados Muñoz, S. Rebollo Acebes, Á. Fernández Martínez, S. Moreno Aliaga, L. Herrera Para, J. Murcia Payá, F. Rodríguez Mulero, P. Guerci, Y. Ince, P. Heeman, B. Ergin, Z. Uz, M. Massey, R. Papatella, E. Bulent, F. Toraman, E. R. Longbottom, H. D. Torrance, H. C. Owen, C. J. Hinds, R. M. Pearse, M. J. O’Dywer, Z. Trogrlic, M. van der Jagt, H. Lingsma, H. H. Ponssen, J. F. Schoonderbeek, F. Schreiner, S. J. Verbrugge, S. Duran, T. van Achterberg, J. Bakker, D. A. M. P. J. Gommers, E. Ista, A. Krajčová, P. Waldauf, F. Duška, A. Shah, N. Roy, S. McKechnie, C. Doree, S. Fisher, S. J. Stanworth, J. F. Jensen, D. Overgaard, M. H. Bestle, D. F. Christensen, I. Egerod, The RAPIT Group, A. Pivkina, I. Zhivotneva, N. Pasko, A. Alklit, R. L. Hansen, H. Knudsen, L. B. Grode, The RAPIT group, M. Hravnak, L. Chen, A. Dubrawski, M. R. Pinsky, S. M. Parry, L. D. Knight, B. C. Connolly, C. E. Baldwin, Z. A. Puthucheary, L. Denehy, N. Hart, P. E. Morris, J. Mortimore, C. L. Granger, H. I. Jensen, R. Piers, B. Van den Bulcke, J. Malmgren, V. Metaxa, A. K. Reyners, M. Darmon, K. Rusinova, D. Talmor, A. P. Meert, L. Cancelliere, L. Zubek, P. Maia, A. Michalsen, J. Decruyenaere, E. Kompanje, S. Vanheule, E. Azoulay, S. Vansteelandt, D. Benoit, C. Ryan, D. Dawson, J. Ball, K. Noone, B. Aisling, S. Prudden, A. Ntantana, D. Matamis, S. Savvidou, M. Giannakou, M. Gouva, G. Nakos, V. Koulouras, J. Aron, G. Lumley, D. Milliken, K. Dhadwal, B. A. McGrath, S. J. Lynch, B. Bovento, G. Sharpe, E. Grainger, S. Pieri-Davies, S. Wallace, B. McGrath, M. Jung, J. Cho, H. Park, G. Suh, O. Kousha, J. Paddle, L. Gamrin Gripenberg, M. Sundström Rehal, J. Wernerman, O. Rooyackers, H. J. de Grooth, W. P. Choo, A. M. Spoelstra-de Man, E. L. Swart, L. Talan, G. Güven, N. D. Altıntas, M. Padar, G. Uusvel, L. Starkopf, J. Starkopf, A. Reintam Blaser, M. S. Kalaiselvan, A. S. Arunkumar, M. K. Renuka, R. L. Shivkumar, M. Volbeda, D. ten Kate, M. Hoekstra, J. M. van der Maaten, M. W. Nijsten, A. Komaromi, Å. Norberg, M. Smedberg, M. Mori, L. Pettersson, M. Theodorakopoulou, T. Christodoulopoulou, A. Diamantakis, F. Frantzeskaki, M. Kontogiorgi, E. Chrysanthopoulou, M. Lygnos, C. Diakaki, A. Armaganidis, K. Gundogan, E. Dogan, R. Coskun, S. Muhtaroglu, M. Sungur, T. Ziegler, M. Guven, A. Kleyman, W. Khaliq, D. Andreas, M. Singer, R. Meierhans, R. Schuepbach, I. De Brito-Ashurst, G. Sabetian, R. Nikandish, F. Hagar, M. Masjedi, B. Maghsudi, A. Vazin, E. Asadpour, K. C. Kao, L. C. Chiu, C. Y. Hung, C. H. Chang, S. H. Li, H. C. Hu, S. El Maraghi, M. Ali, D. Rageb, M. Helmy, J. Marin-Corral, C. Vilà, A. Vàzquez, I. Martín-Loeches, E. Díaz, J. C. Yébenes, A. Rodriguez, F. Álvarez-Lerma, H1N1 SEMICYUC/GETGAG Working Group, N. Varga, A. Cortina-Gutiérrez, L. Dono, M. Martínez-Martínez, C. Maldonado, E. Papiol, M. Pérez-Carrasco, R. Ferrer, K. Nweze, B. Morton, I. Welters, M. Houard, B. Voisin, G. Ledoux, S. Six, E. Jaillette, S. Nseir, S. Romdhani, R. Bouneb, D. Loghmari, N. Ben Aicha, J. Ayachi, K. Meddeb, I. Chouchène, A. Khedher, M. Boussarsar, K. S. Chan, W. L. Yu, J. Nolla, L. Vidaur, J. Bonastre, B. Suberbiola, J. E. Guerrero, H1N1 SEMICYUC/GETGAG working group, N. Ramon Coll, G. Jiménez Jiménez, J. Codina Calero, M. García, M. C. de la Torre, E. Vendrell, E. Palomera, E. Güell, M. Serra-Prat, J. F. Bermejo-Martín, J. Almirall, E. Tomas, A. Escoval, F. Froe, M. H. Vitoria Pereira, N. Velez, E. Viegas, E. Filipe, C. Groves, M. Reay, A. Ballin, F. Facchin, G. Sartori, F. Zarantonello, E. Campello, C. M. Radu, S. Rossi, C. Ori, P. Simioni, N. Umei, I. Shingo, A. C. Santos, C. Candeias, I. Moniz, R. Marçal, Z. Costa e Silva, J. M. Ribeiro, J. F. Georger, J. P. Ponthus, M. Tchir, V. Amilien, M. Ayoub, E. Barsam, G. Martucci, G. Panarello, F. Tuzzolino, G. Capitanio, V. Ferrazza, T. Carollo, L. Giovanni, A. Arcadipane, M. López Sánchez, M. A. González-Gay, F. J. Llorca Díaz, M. I. Rubio López, E. Zogheib, L. Villeret, J. Nader, M. Bernasinski, P. Besserve, T. Caus, H. Dupont, P. Morimont, S. Habran, R. Hubert, T. Desaive, F. Blaffart, N. Janssen, J. Guiot, A. Pironet, P. Dauby, B. Lambermont, T. Pettenuzzo, G. Citton, C. Kirakli, O. Ediboglu, S. Ataman, M. Yarici, F. Tuksavul, S. Keating, A. Gibson, M. Gilles, M. Dunn, G. Price, N. Young, P. Remeta, P. Bishop, M. D. Fernández Zamora, J. Muñoz-Bono, E. Curiel-Balsera, E. Aguilar-Alonso, R. Hinojosa, A. Gordillo-Brenes, J. A. Arboleda-Sánchez, ARIAM-CARDIAC SURGERY PROJECT AUTHORS, I. Skorniakov, D. Vikulova, C. Whiteley, O. Shaikh, A. Jones, M. Ostermann, L. Forni, M. Scott, J. Sahatjian, W. Linde-Zwirble, D. Hansell, P. Laoveeravat, N. Srisawat, M. Kongwibulwut, S. Peerapornrattana, N. Suwachittanont, T. O. Wirotwan, P. Chatkaew, P. Saeyub, K. Latthaprecha, K. Tiranathanagul, S. Eiam-ong, J. A. Kellum, R. E. Berthelsen, A. Perner, A. E. K. Jensen, J. U. Jensen, D. J. Gebhard, J. Price, C. E. Kennedy, A. Akcan-Arikan, Y. R. Kang, M. N. Nakamae, K. Hamed, M. M. Khaled, R. Aly Soliman, M. Sherif Mokhtar, G. Seller-Pérez, D. Arias-Verdú, E. Llopar-Valdor, I. De-Diós-Chacón, G. Quesada-García, M. E. Herrera-Gutierrez, R. Hafes, G. Carroll, P. Doherty, C. Wright, I. G. Guerra Vera, M. Ralston, M. L. Gemmell, A. MacKay, E. Black, R. I. Docking, R. Appleton, M. R. Ralston, L. Gemmell, A. Mackay, J. G. Röttgering, P. W. G. Elbers, N. Mejeni, J. Nsiala, A. Kilembe, P. Akilimali, G. Thomas, A. E. Andersson, A. M. Fagerdahl, V. Knudsen, P-INFECT, A. Ben Cheikh, Y. Hamdaoui, A. Guiga, N. Fraj, N. Sma, I. Chouchene, N. Bouafia, A. Amirian, B. Ziaian, C. Fleischmann, D. O. Thomas-Rueddel, A. Schettler, D. Schwarzkopf, A. Stacke, K. Reinhart, A. Martins, P. Sousa, G. Snell, R. Matsa, T. T. S. Paary, A. M. Cavalheiro, L. L. Rocha, C. S. Vallone, A. Tonilo, M. D. S. Lobato, D. T. Malheiro, G. Sussumo, N. M. Lucino, V. D. Rosenthal, A. Sanaei Dashti, A. Yousefipour, J. R. Goodall, M. Williamson, E. Tant, N. Thomas, C. Balci, C. Gonen, E. Haftacı, H. Gurarda, E. Karaca, B. Paldusová, I. Zýková, D. Šímová, S. Houston, L. D’Antona, J. Lloyd, V. Garnelo-Rey, M. Sosic, V. Sotosek-Tokmazic, J. Kuharic, I. Antoncic, S. Dunatov, A. Sustic, C. T. Chong, M. Sim, T. Lyovarin, F. M. Acosta Díaz, S. Narbona Galdó, M. Muñoz Garach, O. Moreno Romero, A. M. Pérez Bailón, A. Carranza Pinel, M. Colmenero, A. Gritsan, A. Gazenkampf, E. Korchagin, N. Dovbish, R. M. Lee, M. P. P. Lim, B. C. L. Lim, J. J. See, R. Assis, F. Filipe, N. Lopes, L. Pessoa, T. Pereira, N. Catorze, M. S. Aydogan, C. Aldasoro, P. Marchio, A. Jorda, M. D. Mauricio, S. Guerra-Ojeda, M. Gimeno-Raga, M. Colque-Cano, A. Bertomeu-Artecero, M. Aldasoro, S. L. Valles, D. Tonon, T. Triglia, J. C. Martin, M. C. Alessi, N. Bruder, P. Garrigue, L. Velly, S. Spina, V. Scaravilli, C. Marzorati, E. Colombo, D. Savo, A. Vargiolu, G. Cavenaghi, G. Citerio, A. H. V. Andrade, P. Bulgarelli, J. A. P. Araujo, V. Gonzalez, V. A. Souza, C. Massant, C. A. C. Abreu Filho, R. A. Morbeck, L. E. Burgo, R. van Groenendael, L. T. van Eijk, G. P. Leijte, B. Koeneman, M. Kox, P. Pickkers, A. García-de la Torre, M. de la Torre-Prados, A. Fernández-Porcel, C. Rueda-Molina, P. Nuevo-Ortega, T. Tsvetanova-Spasova, E. Cámara-Sola, A. García-Alcántara, L. Salido-Díaz, X. Liao, T. Feng, J. Zhang, X. Cao, Q. Wu, Z. Xie, H. Li, Y. Kang, M. S. Winkler, A. Nierhaus, E. Mudersbach, A. Bauer, L. Robbe, C. Zahrte, E. Schwedhelm, S. Kluge, C. Zöllner, E. Mitsi, S. H. Pennington, J. Reine, A. D. Wright, R. Parker, I. D. Welters, J. D. Blakey, G. Rajam, E. W. Ades, D. M. Ferreira, D. Wang, A. Kadioglu, S. B. Gordon, R. Koch, J. Rahamat-Langedoen, J. Schloesser, M. de Jonge, J. Bringue, R. Guillamat-Prats, E. Torrents, M. L. Martinez, M. Camprubí-Rimblas, L. Blanch, S. Y. Park, Y. B. Park, D. K. Song, S. Shrestha, S. H. Park, Y. Koh, M. J. Park, C. W. Hong, O. Lesur, D. Coquerel, X. Sainsily, J. Cote, T. Söllradl, A. Murza, L. Dumont, R. Dumaine, M. Grandbois, P. Sarret, E. Marsault, D. Salvail, M. Auger-Messier, F. Chagnon, Apelin Group, M. P. Lauretta, E. Greco, A. Dyson, S. Preau, M. Ambler, A. Sigurta, S. Saeed, L. Topcu Sarıca, N. Zibandeh, D. Genc, F. Gul, T. Akkoc, E. Kombak, L. Cinel, I. Cinel, S. J. Pollen, N. Arulkumaran, G. Warnes, D. J. Pennington, K. Brohi, M. J. O’Dwyer, H. Y. Kim, S. Na, J. Kim, Y. F. Chang, A. Chao, P. Y. Shih, C. T. Lee, Y. C. Yeh, L. W. Chen, M. Adriaanse, W. Rietdijk, S. Funcke, S. Sauerlaender, B. Saugel, H. Pinnschmidt, D. A. Reuter, R. Nitzschke, S. Perbet, C. Biboulet, A. Lenoire, D. Bourdeaux, B. Pereira, B. Plaud, J. E. Bazin, V. Sautou, A. Mebazaa, J. M. Constantin, M. Legrand, Y. Boyko, P. Jennum, M. Nikolic, H. Oerding, R. Holst, P. Toft, H. K. Nedergaard, T. Haberlandt, S. Park, S. Kim, Y. J. Cho, Y. J. Lim, A. Chan, S. Tang, S. L. Nunes, S. Forsberg, H. Blomqvist, L. Berggren, M. Sörberg, T. Sarapohja, C. J. Wickerts, J. G. M. Hofhuis, L. Rose, B. Blackwood, E. Akerman, J. Mcgaughey, M. Fossum, H. Foss, E. Georgiou, H. J. Graff, M. Kalafati, R. Sperlinga, A. Schafer, A. G. Wojnicka, P. E. Spronk, F. Khalili, R. Afshari, H. Haddad Khodaei, S. Javadpour, P. Petramfar, S. Nasimi, H. Tabei, A. Gunther, J. O. Hansen, P. Sackey, H. Storm, J. Bernhardsson, Ø. Sundin, A. Bjärtå, A. Bienert, P. Smuszkiewicz, P. Wiczling, K. Przybylowski, A. Borsuk, I. Trojanowska, J. Matysiak, Z. Kokot, M. Paterska, E. Grzeskowiak, A. Messina, E. Bonicolini, D. Colombo, G. Moro, S. Romagnoli, A. R. De Gaudio, F. Della Corte, S. M. Romano, J. A. Silversides, E. Major, E. E. Mann, A. J. Ferguson, D. F. Mcauley, J. C. Marshall, J. A. Diaz-Rodriguez, R. Silva-Medina, E. Gomez-Sandoval, N. Gomez-Gonzalez, R. Soriano-Orozco, P. L. Gonzalez-Carrillo, M. Hernández-Flores, K. Pilarczyk, J. Lubarksi, D. Wendt, F. Dusse, J. Günter, B. Huschens, E. Demircioglu, H. Jakob, A. Palmaccio, A. M. Dell’Anna, D. L. Grieco, F. Torrini, C. Iaquaniello, F. Bongiovanni, M. Antonelli, L. Toscani, D. Antonakaki, D. Bastoni, M. Jozwiak, F. Depret, J. L. Teboul, J. Alphonsine, C. Lai, C. Richard, X. Monnet, G. Demeter, I. Kertmegi, A. Hasanin, A. Lotfy, A. El-adawy, H. Nassar, S. Mahmoud, A. Abougabal, A. Mukhtar, F. Quinty, S. Habchi, A. Luzi, E. Antok, G. Hernandez, B. Lara, L. Enberg, M. Ortega, P. Leon, C. Kripper, P. Aguilera, E. Kattan, M. Lehmann, S. Sakka, B. Bein, R. M. Schmid, J. Preti, J. Creteur, A. Herpain, J. Marc, F. Trojette, S. Bar, L. Kontar, D. Titeca, J. Richecoeur, B. Gelee, N. Verrier, R. Mercier, E. Lorne, J. Maizel, M. Slama, M. E. Abdelfattah, A. Eladawy, M. A. Ali Elsayed, A. Pedraza Montenegro, E. Monares Zepeda, J. Franco Granillo, J. S. Aguirre Sánchez, G. Camarena Alejo, A. Rugerio Cabrera, A. A. Tanaka Montoya, C. Lee, F. Hatib, M. Cannesson, P. Theerawit, T. Morasert, Y. Sutherasan, G. Zani, S. Mescolini, M. Diamanti, R. Righetti, A. Scaramuzza, M. Papetti, M. Terenzoni, C. Gecele, M. Fusari, K. A. Hakim, A. Chaari, M. Ismail, A. H. Elsaka, T. M. Mahmoud, K. Bousselmi, V. Kauts, W. F. Casey, S. D. Hutchings, D. Naumann, J. Wendon, S. Watts, E. Kirkman, Z. Jian, S. Buddi, J. Settels, P. Bertini, F. Guarracino, C. Trepte, P. Richter, S. A. Haas, V. Eichhorn, J. C. Kubitz, M. S. Soliman, W. I. Hamimy, A. Z. Fouad, A. M. Mukhtar, M. Charlton, L. Tonks, L. Mclelland, T. J. Coats, J. P. Thompson, M. R. Sims, D. Williams, D. Z. Roushdy, R. A. Soliman, R. A. Nahas, M. Y. Arafa, W. T. Hung, C. C. Chiang, W. C. Huang, K. C. Lin, S. C. Lin, C. C. Cheng, P. L. Kang, S. R. Wann, G. Y. Mar, C. P. Liu, M. Lopez Carranza, H. Sancho Fernandez, J. A. Sanchez Roman, F. Lucena, A. Campanario Garcia, A. Loza Vazquez, A. Lesmes Serrano, ARIAM-SEMICYUC Registry Investigators, L. Sayagues Moreira, R. Vidal-Perez, U. Anido Herranz, J. M. Garcia Acuna, C. Pena Gil, J. L. Garcia Allut, P. Rascado Sedes, C. Martin Lopez, E. Saborido Paz, C. Galban Rodriguez, J. R. Gonzalez-Juanatey, A. Vallejo-Baez, M. V. de la Torre-Prados, ARIAM Group, R. Marharaj, K. Gervasio, M. Bottiroli, M. Mondino, D. De Caria, A. Calini, E. Montrasio, F. Milazzo, M. P. Gagliardone, A. Vallejo-Báez, ARIAM group, U. Anido, M. Cheikh-Bouhlel, M. P. R. D. L. Dela Cruz, J. M. Bernardo, F. Galfo, A. Marino, C. C. Chao, P. Hou, C. C. Hung, C. H. Chiang, Y. J. Liou, S. M. Hung, Y. S. Lin, F. Y. Kuo, K. R. Chiou, C. J. Chen, L. S. Yan, C. Y. Liu, H. H. Wang, H. L. Chen, C. K. Ho, S. Grewal, S. Gopal, C. Corbett, A. Wilson, J. Capps, W. Ayoub, A. Lomas, S. Ghani, J. Moore, D. Atkinson, M. Sharman, W. Swinnen, J. Pauwels, K. Mignolet, E. Pannier, A. Koch, T. Sarens, W. Temmerman, A. M. Elmenshawy, A. M. Fayed, M. Elboriuny, E. Hamdy, E. Zakaria, A. C. Falk, A. Petosic, K. Olafsen, H. Wøien, H. Flaatten, K. Sunde, J. J. Cáceres Agra, J. L. Santana Cabrera, J. D. Martín Santana, L. Melián Alzola, H. Rodríguez Pérez, T. Castro Pires, H. Calderón, A. Pereira, S. Castro, C. Granja, I. Norkiene, I. Urbanaviciute, G. Kezyte, D. Ringaitiene, T. Jovaisa, G. Vogel, U. B. Johansson, A. Sandgren, C. Svensen, E. Joelsson-Alm, M. A. Leite, L. D. Murbach, E. F. Osaku, C. R. L. M. Costa, M. Pelenz, N. M. Neitzke, M. M. Moraes, J. L. Jaskowiak, M. M. M. Silva, R. S. Zaponi, L. R. L. Abentroth, S. M. Ogasawara, A. C. Jorge, P. A. D. Duarte, J. Barreto, S. T. Duarte, S. Taba, D. Miglioranza, D. P. Gund, C. F. Lordani, H. Vollmer, M. Gager, C. Waldmann, A. T. Mazzeo, R. Tesio, C. Filippini, M. E. Vallero, C. Giolitti, S. Caccia, M. Medugno, T. Tenaglia, R. Rosato, I. Mastromauro, L. Brazzi, P. P. Terragni, R. Urbino, V. Fanelli, V. M. Ranieri, L. Mascia, J. Ballantyne, L. Paton, P. Perez-Teran, O. Roca, J. C. Ruiz-Rodriguez, A. Zapatero, J. Serra, S. Bianzina, P. Cornara, G. Rodi, G. Tavazzi, M. Pozzi, G. A. Iotti, F. Mojoli, A. Braschi, A. Vishnu, D. Buche, R. Pande, D. L. J. Moolenaar, F. Bakhshi-Raiez, D. A. Dongelmans, N. F. de Keizer, D. W. de Lange, I. Fuentes Fernández, D. Martínez Baño, J. L. Buendía Moreno, R. Jara Rubio, J. Scott, D. Phelan, D. Morely, J. O’Flynn, P. Stapleton, M. Lynch, B. Marsh, E. Carton, C. O’Loughlin, K. C. Cheng, M. I. Sung, M. O. Elghonemi, M. H. Saleh, T. S. Meyhoff, M. Krag, P. B. Hjortrup, M. H. Møller, T. Öhman, T. Sigmundsson, E. Redondo, M. Hallbäck, F. Suarez-Sipmann, H. Björne, C. Hällsjö Sander, KARISMA, D. Chiumello, C. Chiurazzi, M. Brioni, I. Algieri, M. Guanziroli, G. Vergani, T. Tonetti, I. Tomic, A. Colombo, F. Crimella, E. Carlesso, V. Gasparovic, R. El-Sherif, M. Abd Al-Basser, A. Raafat, A. El-Sherif, L. R. A. Schouten, O. L. Cremer, D. S. Y. Ong, G. Amoruso, G. Cinnella, L. D. J. Bos, P. Schmidle, M. Findeisen, P. Hoppmann, J. Jaitner, F. Brettner, T. Lahmer, EXODUS-investigators, G. Rajagopalan, V. Bansal, R. Frank, R. Hinds, J. Levitt, United States Critical Illness and Injury Trials Group/LIPS-B investigators, S. Siddiqui, SICM NICER Group, J. P. Gilbert, K. Sim, C. H. Wang, I. J. Li, W. R. Tang, P. Persona, A. De Cassai, M. Franco, A. Goffi, B. Llorente Ruiz, J. Lujan Varas, R. Molina Montero, C. Pintado Delgado, O. Navarrete, M. Vazquez Mezquita, E. Alonso Peces, M. A. M. Nakamura, L. A. Hajjar, F. R. B. G. Galas, T. A. Ortiz, M. B. P. Amato, L. Bitker, N. Costes, D. Le Bars, F. Lavenne, D. Mojgan, J. C. Richard, D. Massari, M. Gotti, P. Cadringher, A. Zerman, M. Türkoğlu, G. Arık, F. Yıldırım, Z. Güllü, I. Kara, N. Boyacı, B. Basarık Aydoğan, Ü. Gaygısız, K. Gönderen, G. Aygencel, M. Aydoğdu, Z. Ülger, G. Gürsel, J. Riera, C. Maldonado Toral, C. Mazo, M. Martínez, J. Baldirà, L. Lagunes, A. Roman, M. Deu, J. Rello, D. J. Levine, R. M. Mohus, Å. Askim, J. Paulsen, A. Mehl, A. T. Dewan, J. K. Damås, E. Solligård, B. O. Åsvold, Mid-Norway Sepsis Research Center, A. DeWan, O. Aktepe, A. Kara, H. Yeter, A. Topeli, M. Norrenberg, M. Devroey, H. Khader, J. C. Preiser, Z. Tang, C. Qiu, L. Tong, C. Cai, O. Apostolopoulou, J. Y. Moon, M. R. Park, I. S. Kwon, G. R. Chon, J. Y. Ahn, S. J. Kwon, Y. J. Chang, J. Y. Lee, S. Y. Yoon, J. W. Lee, The Korean Chungcheong Critical Care Research Group, M. Kostalas, J. Mckinlay, G. Kooner, G. Dudas, A. Horton, C. Kerr, N. Karanjia, B. Creagh-Brown, N. D. Altintas, S. Izdes, O. Keremoglu, A. Alkan, S. Neselioglu, O. Erel, N. Tardif, T. Gustafsson, K. N. MacEachern, M. Traille, I. Bromberg, S. E. Lapinsky, M. J. Moore, J. L. García-Garmendia, F. Villarrasa-Clemente, F. Maroto-Monserrat, O. Rufo-Tejeiro, V. Jorge-Amigo, M. Sánchez-Santamaría, C. Colón-Pallarés, A. Barrero-Almodóvar, S. Gallego-Lara, C. T. Anthon, R. B. Müller, N. Haase, K. Møller, J. Wetterslev, M. Nakanishi, A. Kuriyama, T. Fukuoka, M. A. Abd el Halim, M. H. Elsaid hafez, A. M. Moktar, H. M. Elazizy, K. Abdel Hakim, M. Elbahr, T. Mahmoud, E. Khalil, W. Casey, S. H. Zaky, A. Rizk, R. Ahmed, G. A. Ospina-Tascón, A. F. Garcia Marin, G. J. Echeverry, W. F. Bermudez, H. J. Madriñan-Navia, J. D. Valencia, E. Quiñonez, A. Marulanda, C. A. Arango-Dávila, A. Bruhn, D. De Backer, D. Orbegozo Cortes, F. Su, J. L. Vincent, L. Tullo, L. Mirabella, P. Di Molfetta, M. Dambrosio, C. Villavicencio Lujan, J. Leache irigoyen, M. Cartanya ferré, R. Carbonell García, M. Ahmed, M. El Ayashi, E. Ayman, M. Salem, S. Fathy, A. Zaghlol, M. F. Aguilar Arzapalo, Å. Valsø, T. Rustøen, I. Schou-Bredal, L. Skogstad, K. Tøien, C. Padilla, Y. Palmeiro, W. Egbaria, R. Kigli, B. Maertens, K. Blot, S. Blot, E. Santana-Santos, E. R. dos Santos, R. E. D. L. Ferretti-Rebustini, R. D. C. C. D. O. dos Santos, R. G. S. Verardino, L. A. Bortolotto, A. M. Doyle, I. Naldrett, J. Tillman, S. Price, P. Pearson, J. Greaves, D. Goodall, A. Berry, A. Richardson, G. O. Odundo, P. Omengo, P. Obonyo, N. M. Chanzu, R. Kleinpell, S. J. Sarris, P. Nedved, M. Heitschmidt, H. Ben-Ghezala, S. Snouda, S. Djobbi, N. K. J. Adhikari, D. Leasa, D. Fergusson, D. A. Mckim, J. Weblin, D. McWilliams, F. Doesburg, F. Cnossen, W. Dieperink, W. Bult, M. W. N. Nijsten, G. A. Galvez-Blanco, C. I. Olvera Guzman, J. Santos Stroud, R. Thomson, M. Llaurado-Serra, A. Lobo-Civico, M. Pi-Guerrero, I. Blanco-Sanchez, A. Piñol-Tena, C. Paños-Espinosa, Y. Alabart-Segura, B. Coloma-Gomez, A. Fernandez-Blanco, F. Braga-Dias, M. Treso-Geira, A. Valeiras-Valero, L. Martinez-Reyes, A. Sandiumenge, M. F. Jimenez-Herrera, CAPCRI Study, R. Prada, P. Juárez, R. Argandoña, J. J. Díaz, C. Sánchez Ramirez, P. Saavedra, S. Ruiz Santana, O. Obukhova, S. Kashiya, I. A. Kurmukov, A. M. Pronina, P. Simeone, L. Puybasset, G. Auzias, O. Coulon, B. Lesimple, G. Torkomian, A. Bartkowska-Sniatkowska, O. Szerkus, D. Siluk, J. Bartkowiak-Wieczorek, J. Rosada-Kurasinska, J. Warzybok, R. Kaliszan, C. Hernandez Caballero, S. Roberts, G. Isgro, D. Hall, G. Guillaume, O. Passouant, F. Dumas, W. Bougouin, B. Champigneulle, M. Arnaout, J. Chelly, J. D. Chiche, O. Varenne, J. P. Mira, E. Marijon, A. Cariou, M. Beerepoot, H. R. Touw, K. Parlevliet, C. Boer, P. W. Elbers, Á. J. Roldán Reina, Y. Corcia Palomo, R. Martín Bermúdez, L. Martín Villén, I. Palacios García, J. R. Naranjo Izurieta, J. B. Pérez Bernal, F. J. Jiménez Jiménez, Cardiac Arrest Group HUVR, F. Cota-Delgado, T. Kaneko, H. Tanaka, M. Kamikawa, R. Karashima, S. Iwashita, H. Irie, S. Kasaoka, O. Arola, R. Laitio, A. Saraste, J. Airaksinen, M. Pietilä, M. Hynninen, J. Wennervirta, M. Bäcklund, E. Ylikoski, P. Silvasti, E. Nukarinen, J. Grönlund, V. P. Harjola, J. Niiranen, K. Korpi, M. Varpula, R. O. Roine, T. Laitio, for the Xe-HYPOTHECA study group, S. Salah, B. G. Hassen, A. Mohamed Fehmi, Y. C. Hsu, J. Barea-Mendoza, C. García-Fuentes, M. Castillo-Jaramillo, H. Dominguez-Aguado, R. Viejo-Moreno, L. Terceros-Almanza, S. Bermejo Aznárez, C. Mudarra-Reche, W. Xu, M. Chico-Fernández, J. C. Montejo-González, K. Crewdson, M. Thomas, M. Merghani, L. Fenner, P. Morgan, D. Lockey, E. J. van Lieshout, B. Oomen, J. M. Binnekade, R. J. de Haan, N. P. Juffermans, M. B. Vroom, R. Algarte, L. Martínez, B. Sánchez, I. Romero, F. Martínez, S. Quintana, J. Trenado, O. Sheikh, D. Pogson, R. Clinton, F. Riccio, A. Arthur, L. Young, A. Sinclair, D. Markopoulou, K. Venetsanou, L. Filippou, E. Salla, S. Stratouli, I. Alamanos, A. H. Guirgis, R. Gutiérrez Rodriguez, M. J. Furones Lorente, I. Macias Guarasa, A. Ukere, S. Meisner, G. Greiwe, B. Opitz, D. Benten, B. Nashan, L. Fischer, C. J. C. Trepte, C. R. Behem, B. Ana, A. Vazir, D. Gibson, M. R. Hadavi, M. Riahi alam, M. R. Sasani, N. Parenti, F. Agrusta, C. Palazzi, B. Pifferi, R. Sganzerla, F. Tagliazucchi, A. Luciani, M. Möller, J. Müller-Engelmann, G. Montag, P. Adams, C. Lange, J. Neuzner, R. Gradaus, K. H. Wodack, F. Thürk, A. D. Waldmann, M. F. Grässler, S. Nishimoto, S. H. Böhm, E. Kaniusas, C. J. Trepte, M. Wallin, F. Suarez Sipman, A. Oldner, L. Colinas, R. Vicho, M. Serna, R. Cuena, A. Canabal, ECOCRITIC group, M. Etman, M. El Bahr, A. El Sakka, A. Arali, O. Bond, P. De Santis, E. Iesu, F. Franchi, S. Scolletta, F. S. Taccone, Z. Marutyan, L. Hamidova, A. Shakotko, V. Movsisyan, I. Uysupova, A. Evdokimov, S. Petrikov, F. J. Redondo Calvo, N. Bejarano, V. Baladron, R. Villazala, J. Redondo, D. Padilla, P. Villarejo, C. Gomez-Gonzalez, S. Mas-Font, A. Puppo-Moreno, M. Herrera-Gutierrez, M. Garcia-Garcia, S. Aldunate-Calvo, NEFROCON Investigators, E. P. Plata-Menchaca, X. L. Pérez-Fernández, M. Estruch, A. Betbese-Roig, P. Cárdenas Campos, M. Rojas Lora, N. D. Toapanta Gaibor, R. S. Contreras Medina, V. D. Gumucio Sanguino, E. J. Casanova, J. Sabater Riera, SIRAKI group, K. Kritmetapak, S. Peerapornratana, P. Kittiskulnam, T. Dissayabutra, P. Susantithapong, K. Praditpornsilpa, K. Tungsanga, S. Eiam-Ong, T. Winkelmann, T. Busch, J. Meixensberger, S. Bercker, E. M. Flores Cabeza, M. Sánchez Sánchez, N. Cáceres Giménez, C. Gutierrez Melón, E. Herrero de Lucas, P. Millán Estañ, M. Hernández Bernal, A. Garcia de Lorenzo y Mateos, P. A. C. Specht, M. Balik, M. Zakharchenko, F. Los, H. Brodska, C. de Tymowski, P. Augustin, M. Desmard, P. Montravers, S. N. Stapel, R. de Boer, H. M. Oudemans, A. Hollinger, T. Schweingruber, F. Jockers, M. Dickenmann, M. Siegemund, Clinical Intensive Care Research Basel, N. Runciman, L. Alban, C. Turrini, T. Sasso, T. Langer, P. Taccone, C. Marenghi, G. Grasselli, P. Wibart, T. Reginault, M. Garcia, B. Barbrel, A. Benard, C. Bader, F. Vargas, H. N. Bui, G. Hilbert, J. M. Serrano Simón, P. Carmona Sánchez, F. Ruiz Ferrón, M. García de Acilu, J. Marin, V. Antonia, L. Ruano, M. Monica, G. Hong, D. H. Kim, Y. S. Kim, J. S. Park, Y. K. Jee, Z. Yu xiang, W. Jia-xing, W. Xiao dan, N. Wen long, W. Yu, Z. Yan, X. Cheng, T. Kobayashi, Y. Onodera, R. Akimoto, A. Sugiura, H. Suzuki, M. Iwabuchi, M. Nakane, K. Kawamae, P. Carmona Sanchez, M. D. Bautista Rodriguez, M. Rodriguez Delgado, V. Martínez de Pinillos Sánchez, A. Mula Gómez, P. Beuret, C. Fortes, M. Lauer, M. Reboul, J. C. Chakarian, X. Fabre, B. Philippon-Jouve, S. Devillez, M. Clerc, N. Rittayamai, M. Sklar, M. Dres, M. Rauseo, C. Campbell, B. West, D. E. Tullis, M. Okada, N. Ahmad, M. Wood, A. Glossop, J. Higuera Lucas, A. Blandino Ortiz, D. Cabestrero Alonso, R. De Pablo Sánchez, L. Rey González, R. Costa, G. Spinazzola, A. Pizza, G. Ferrone, M. Rossi, G. Conti, H. Ribeiro, J. Alves, M. Sousa, P. Reis, C. S. Socolovsky, R. P. Cauley, J. E. Frankel, A. L. Beam, K. O. Olaniran, F. K. Gibbons, K. B. Christopher, J. Pennington, P. Zolfaghari, H. S. King, H. H. Y. Kong, H. P. Shum, W. W. Yan, C. Kaymak, N. Okumus, A. Sari, B. Erdogdu, S. Aksun, H. Basar, A. Ozcan, N. Ozcan, D. Oztuna, J. A. Malmgren, S. Lundin, K. Torén, M. Eckerström, A. Wallin, A. C. Waldenström, for the Section on Ethics of the ESICM, F. C. Riccio, A. C. P. Antonio, A. F. Leivas, F. Kenji, E. James, S. Jonnada, C. S. Gerrard, N. Jones, J. D. Salciccioli, D. C. Marshall, M. Komorowski, A. Hartley, M. C. Sykes, R. Goodson, J. Shalhoub, J. R. Fernández Villanueva, R. Fernández Garda, A. M. López Lago, E. Rodríguez Ruiz, R. Hernández Vaquero, C. Galbán Rodríguez, E. Varo Pérez, C. Hilasque, I. Oliva, G. Sirgo, M. C. Martin, M. Olona, M. C. Gilavert, M. Bodí, C. Ebm, G. Aggarwal, S. Huddart, N. Quiney, S. M. Fernandes, J. Santos Silva, J. Gouveia, D. Silva, R. Marques, H. Bento, A. Alvarez, Z. Costa Silva, D. Díaz Diaz, M. Villanova Martínez, E. Palencia Herrejon, A. Martinez de la Gandara, G. Gonzalo, M. A. Lopez, P. Ruíz de Gopegui Miguelena, C. I. Bernal Matilla, P. Sánchez Chueca, M. D. C. Rodríguez Longares, R. Ramos Abril, A. L. Ruíz Aguilar, R. Garrido López de Murillas, R. Fernández Fernández, P. Morales Laborías, M. A. Díaz Castellanos, M. E. Morales Laborías, J. Park, S. Woo, T. West, E. Powell, A. Rimmer, C. Orford, J. Williams, P. Ruiz de Gopegui Miguelena, R. S. Bourne, R. Shulman, M. Tomlin, G. H. Mills, M. Borthwick, W. Berry, D. García Huertas, F. Manzano, F. Villagrán-Ramírez, A. Ruiz-Perea, C. Rodríguez-Mejías, F. Santiago-Ruiz, M. Colmenero-Ruiz, C. König, B. Matt, A. Kortgen, C. S. Hartog, A. Wong, C. Balan, G. Barker, S. Tachaboon, J. Paratz, G. Kayambu, R. Boots, R. Vlasenko, E. Gromova, S. Loginov, M. Kiselevskiy, Y. Dolgikova, K. B. Tang, C. M. Chau, K. N. Lam, E. Gil, G. Y. Suh, C. M. Park, C. R. Chung, C. H. Lai, Y. J. Cheng, V. Colella, N. Zarrillo, M. D’Amico, F. Forfori, B. Pezza, T. Laddomada, V. Beltramelli, M. L. Pizzaballa, A. Doronzio, B. Balicco, D. Kiers, W. van der Heijden, J. Gerretsen, Q. de Mast, S. el Messaoudi, G. Rongen, M. Gomes, N. P. Riksen, Y. Kashiwagi, K. Hayashi, Y. Inagaki, S. Fujita, A. Blet, M. Sadoune, J. Lemarié, N. Bihry, R. Bern, E. Polidano, R. Merval, J. M. Launay, B. Lévy, J. L. Samuel, J. Hartmann, S. Harm, and V. Weber

Subjects
Medical emergencies. Critical care. Intensive care. First aid, RC86-88.9
Published
2016
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26. SHMT2 inhibition disrupts the TCF3 transcriptional survival program in Burkitt lymphoma

Author

Sebastian Wolf, Constanze Schneider, Roland Schmitz, Kwang Seok Lee, Mikolaj Slabicki, Hans Christian Reinhardt, Henning Urlaub, Craig J. Thomas, Anne C. Wilke, Hubert Serve, Fernando Kreuz, Joshua D. Rabinowitz, Dominique Jahn, Michele Ceribelli, Christian Brandts, Kimberly Stegmaier, Matthew G. Vander Heiden, Caroline A. Lewis, Thomas Oellerich, Kamil Bojarczuk, Thorsten Zenz, Daniel J. Hodson, Sara A Rieke, Yana Pikman, James Q Wang, Xincheng Xu, Michael Engelke, Hahn Kim, Hanibal Bohnenberger, Zana A. Coulibaly, Clemens A Schmitt, Federico Comoglio, James D. Phelan, Louis M. Staudt, Carmen Doebele, Sebastian Scheich, Björn Chapuy, Frank Schnuetgen, Gero Knittel, Frances A. Tosto, Philipp Stroebel, Alena Zindel, Björn Häupl, Philipp Stauder, and Thanh Hung Dang

Subjects
Cancer Research, Formates, Cell Survival, Immunology, Glycine, Medizin, Aggressive lymphoma, Biology, Biochemistry, Mice, 03 medical and health sciences, 0302 clinical medicine, Cell Line, Tumor, Drug Discovery, Basic Helix-Loop-Helix Transcription Factors, medicine, Animals, Humans, Molecular Targeted Therapy, Transcription factor, PI3K/AKT/mTOR pathway, 030304 developmental biology, Glycine Hydroxymethyltransferase, 0303 health sciences, Gene knockdown, Lymphoid Neoplasia, Autophagy, breakpoint cluster region, Cell Biology, Hematology, medicine.disease, Burkitt Lymphoma, 3. Good health, Lymphoma, Gene Expression Regulation, Neoplastic, Gene Knockdown Techniques, 030220 oncology & carcinogenesis, TCF3, Mutation, Proteolysis, Cancer research
Abstract

Burkitt lymphoma (BL) is an aggressive lymphoma type that is currently treated by intensive chemoimmunotherapy. Despite the favorable clinical outcome for most patients with BL, chemotherapy-related toxicity and disease relapse remain major clinical challenges, emphasizing the need for innovative therapies. Using genome-scale CRISPR-Cas9 screens, we identified B-cell receptor (BCR) signaling, specific transcriptional regulators, and one-carbon metabolism as vulnerabilities in BL. We focused on serine hydroxymethyltransferase 2 (SHMT2), a key enzyme in one-carbon metabolism. Inhibition of SHMT2 by either knockdown or pharmacological compounds induced anti-BL effects in vitro and in vivo. Mechanistically, SHMT2 inhibition led to a significant reduction of intracellular glycine and formate levels, which inhibited the mTOR pathway and thereby triggered autophagic degradation of the oncogenic transcription factor TCF3. Consequently, this led to a collapse of tonic BCR signaling, which is controlled by TCF3 and is essential for BL cell survival. In terms of clinical translation, we also identified drugs such as methotrexate that synergized with SHMT inhibitors. Overall, our study has uncovered the dependency landscape in BL, identified and validated SHMT2 as a drug target, and revealed a mechanistic link between SHMT2 and the transcriptional master regulator TCF3, opening up new perspectives for innovative therapies.

Published
2022

28. BCL10 Mutants: Architects of Oncogenic Signaling Provide a Blueprint for Precision Medicine

Author

James D. Phelan and Thomas Oellerich

Subjects
Oncology
Abstract

Summary: BCL10, a key activator of NF-κB downstream of oncogenic B-cell receptor signaling, is mutated in nearly 40% of the BN2/C1 genetic subtype of diffuse large B-cell lymphoma, but how these mutations function to augment signaling and their relevance to targeted precision medicine agents remains unclear. In this issue of Cancer Discovery, Xia and colleagues demonstrate distinct mechanisms of oncogenic signaling regulation and therapeutic vulnerabilities among different recurrent BCL10 mutations. See related article by Xia et al., p. 1922 (1).

Published
2022

29. Oxygen Inhomogeneity and Reversibility in Single Crystal LaNiO3−δ

Author

Hong Zheng, Bi-Xia Wang, D. Phelan, Junjie Zhang, Yang Ren, M. J. Krogstad, S. Rosenkranz, R. Osborn, and J. F. Mitchell

Subjects
nickelates, crystal growth, oxygen deficiency, diffraction, Crystallography, QD901-999
Abstract

LaNiO3−δ single crystals have been obtained via high pressure floating zone growth under 149 bar of oxygen pressure. We find a radial gradient in the magnetic properties of specimens extracted from the as-grown boule, which we correlate with the appearance of ordered oxygen vacancy structures. This radial oxygen inhomogeneity has been characterized systematically using a combination of magnetization and X-ray scattering measurements. We establish the presence of rhombohedral ( R 3 ¯ c ), oxygen stoichiometric specimens at the periphery of the boule and the presence of a dilute concentration of ordered oxygen-deficient orthorhombic La2Ni2O5 in the center. Furthermore, we demonstrate that the as-grown, oxygen-deficient central regions of the crystal can be annealed under high oxygen pressure, without loss of crystallinity, into fully oxygenated LaNiO3, recovering magnetic properties that are characteristic of stoichiometric specimens from the exterior region of the crystal. Thus, single crystals of LaNiO3−δ possess oxygen content that can be reversibly modified under oxidizing and reducing conditions.

Published
2020
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30. Bridging the Technology Divide in the COVID-19 Era: Using Virtual Outreach to Expose Middle and High School Students to Imaging Technology

Author

Karen L. Yanowitz, Billy R. Thomas, Gregory R. Snead, Tiffany W. Huitt, Noor Akhter, Mohsin Syed, and Kevin D. Phelan

Subjects
Technology, Engineering, General Immunology and Microbiology, General Chemical Engineering, General Neuroscience, Humans, COVID-19, Students, General Biochemistry, Genetics and Molecular Biology, Minority Groups
Abstract

Increasing the diversity of students choosing careers in science, technology, engineering, and mathematics (STEM) fields is an area of intense focus across the USA, especially in kindergarten through 12th grade (K-12)-focused pipeline programs in medical schools. A diverse STEM workforce contributes to better problem-solving and equity in health care. Two of the many major barriers for rural students are the lack of sufficient STEM role models and limited access to technology in the classroom. Medical schools often serve as an important resource for students in the local community who can easily gain access to STEM professionals and modern technology through on-campus, sponsored events and STEM outreach to the local classrooms. However, underrepresented minority (URM) students often live in socioeconomically distressed parts of rural states such as Arkansas, where access to STEM role models and technology is limited. Virtual learning in the COVID-19 era has proven that the imaging technology resources of a medical school can be harnessed to reach a wider audience, especially students living in rural areas far from the medical school campus.

Published
2022

31. Post-systolic shortening index by echocardiography evaluation of dyssynchrony in the non-dilated and hypertrophied left ventricle

Author

T K M Wang, Y Saijo, N Chan, B Sperry, D Phelan, M Y Desai, B P Griffin, R A Grimm, and Z B Popovic

Subjects
Cardiology and Cardiovascular Medicine
Abstract

Background Post-systolic shortening index (PSI) is defined as myocardial shortening that occurs after aortic valve closure, and is an emerging measure of regional LV contractile dysfunction. PSI measurement variability amongst software vendor and its relationship with mechanical dyssynchrony and mechanical dispersion index (MDI) remains unknown. We evaluated PSI by speckle-tracking echocardiography from several vendors in patients with increased left ventricular wall thickness, and associations with MDI. Methods This is a prospective cross-sectional study of 70 patients (36 hypertrophic cardiomyopathy [HCM], 18 cardiac amyloidosis and 16 healthy controls) undergoing clinically indicated echocardiography. PSI was measured using QLAB/aCMQ (Philips), QLAB/LV auto-trace (Philips), EchoPAC (GE), Velocity Vector Imaging (Siemens), and EchoInsight (EPSILON) software packages, and calculated as 100% × (post systolic strain − end-systole strain)/post systolic strain. Results There was a significant difference in mean PSI among controls 2.1±0.6%, HCM 6.1±2.6% and cardiac amyloidosis 6.8±2.7% (p Conclusion PSI was greater in HCM and cardiac amyloidosis patients than controls, and a valuable tool for dyssynchrony evaluation, with moderate correlations to MDI and strain. However, there were significant variations in PSI measurements by software vendor especially in patients with pathological increase in LV wall thickness, suggesting that separate vendor-specific thresholds for abnormal PSI are required. Funding Acknowledgement Type of funding sources: None.

Published
2022

32. GENETIC SUBGROUPS INFORM ON PATHOBIOLOGY IN ADULT AND PEDIATRIC BURKITT LYMPHOMA

Author

Nicole Thomas, Kostiantyn Dreval, Daniela S. Gerhard, Laura K. Hilton, Jeremy S. Abramson, Richard F. Ambinder, Stefan Barta, Nancy L. Bartlett, Jeffrey Bethony, Kishor Bhatia, Jay Bowen, Anthony C. Bryan, Ethel Cesarman, Corey Casper, Amy Chadburn, Manuela Cruz, Dirk P. Dittmer, Maureen A. Dyer, Pedro Farinha, Julie M. Gastier-Foster, Alina S. Gerrie, Bruno M. Grande, Timothy Greiner, Nicholas B. Griner, Thomas G. Gross, Nancy L. Harris, John D. Irvin, Elaine S. Jaffe, David Henry, Rebecca Huppi, Fabio E. Leal, Michael S. Lee, Jean Paul Martin, Marie-Reine Martin, Sam M. Mbulaiteye, Ronald Mitsuyasu, Vivian Morris, Charles G. Mullighan, Andrew J. Mungall, Karen Mungall, Innocent Mutyaba, Mostafa Nokta, Constance Namirembe, Ariela Noy, Martin D. Ogwang, Abraham Omoding, Jackson Orem, German Ott, Hilary Petrello, Stefania Pittaluga, James D. Phelan, Juan Carlos Ramos, Lee Ratner, Steven J. Reynolds, Paul G. Rubinstein, Gerhard Sissolak, Graham Slack, Shaghayegh Soudi, Steven H. Swerdlow, Alexandra Traverse-Glehen, Wyndham H. Wilson, Jasper Wong, Robert Yarchoan, Jean C. ZenKlusen, Marco A. Marra, Louis M. Staudt, David W. Scott, and Ryan D. Morin

Subjects
Immunology, Cell Biology, Hematology, Biochemistry
Abstract

Burkitt lymphoma (BL) accounts for most pediatric non-Hodgkin lymphomas, being less common but significantly more lethal when diagnosed in adults. Much of the knowledge of the genetics of BL thus far has originated from the study of pediatric BL (pBL), leaving its relationship to adult BL (aBL) and other adult lymphomas not fully explored. We sought to more thoroughly identify the somatic changes that underlie lymphomagenesis in aBL and any molecular features that associate with clinical disparities within and between pBL and aBL. Through comprehensive whole-genome sequencing of 230 BL and 295 diffuse large B-cell lymphoma (DLBCL) tumors, we identified additional significantly mutated genes, including more genetic features that associate with tumor Epstein-Barr virus status, and unraveled new distinct subgroupings within BL and DLBCL with 3 predominantly comprising BLs: DGG-BL (DDX3X, GNA13, and GNAI2), IC-BL (ID3 and CCND3), and Q53-BL (quiet TP53). Each BL subgroup is characterized by combinations of common driver and noncoding mutations caused by aberrant somatic hypermutation. The largest subgroups of BL cases, IC-BL and DGG-BL, are further characterized by distinct biological and gene expression differences. IC-BL and DGG-BL and their prototypical genetic features (ID3 and TP53) had significant associations with patient outcomes that were different among aBL and pBL cohorts. These findings highlight shared pathogenesis between aBL and pBL, and establish genetic subtypes within BL that serve to delineate tumors with distinct molecular features, providing a new framework for epidemiologic, diagnostic, and therapeutic strategies.

Published
2022

33. Changes in Multidisciplinary Tracheostomy Team Practice Over Time

Author

E, Carton, E, Fitzgerald, R, Elebert, C, Malone, S, O'Brien, A, Dunne, R, Ní Muircheartaigh, and D, Phelan

Subjects
Intensive Care Units, Time Factors, Tracheostomy, Patients' Rooms, Humans, Retrospective Studies
Abstract

Aim Increasing numbers of tracheostomy patients are discharged from the Intensive Care Unit (ICU) to general hospital wards. There is evidence that a Multidisciplinary Tracheostomy Team (MTT) can have a positive impact on the care of tracheostomy patients discharged from the ICU. We compared tracheostomy management and patient outcome in two time periods, at the start of our MTT practice in 2009-2011 and again in 2017. Methods In a retrospective audit, we compared tracheostomy management and patient outcome in 117 patients who had a tracheostomy in 2009-2011 with 81 patients who had a tracheostomy in 2017. Results The duration of tracheostomy cannulation was significantly shorter (21 vs 31 days, p=0.0005) in 2017 compared to 2009-2011. A Mini-Trach was used after tracheostomy decannulation in 56 of the 81 (69%) tracheostomy patients in 2017. Conclusions The continued development of our MTT service over 8 years was associated with a significantly shorter duration of tracheostomy cannulation and the introduction of Mini-Trach use after tracheostomy decannulation. These results support the importance of maintaining an active MTT service to manage tracheostomy patients after discharge from the ICU.

Published
2022

34. A CRISPR screen targeting PI3K effectors identifies RASA3 as a negative regulator of LFA-1–mediated adhesion in T cells

Author

Kristoffer H. Johansen, Dominic P. Golec, Bonnie Huang, Chung Park, Julie H. Thomsen, Silvia Preite, Jennifer L. Cannons, Fabien Garçon, Edward C. Schrom, Christina J. F. Courrèges, Tibor Z. Veres, James Harrison, Meritxell Nus, James D. Phelan, Wolfgang Bergmeier, John H. Kehrl, Klaus Okkenhaug, and Pamela L. Schwartzberg

Subjects
T-Lymphocytes, GTPase-Activating Proteins, Cell Biology, Intercellular Adhesion Molecule-1, Biochemistry, Lymphocyte Function-Associated Antigen-1, Article, Mice, Phosphatidylinositol 3-Kinases, Antigens, CD, Cell Adhesion, Animals, Clustered Regularly Interspaced Short Palindromic Repeats, Phosphatidylinositol 3-Kinase, Cell Adhesion Molecules, Molecular Biology
Abstract

The integrin lymphocyte function–associated antigen 1 (LFA-1) helps to coordinate the migration, adhesion, and activation of T cells through interactions with intercellular adhesion molecule 1 (ICAM-1) and ICAM-2. LFA-1 is activated during the engagement of chemokine receptors and the T cell receptor (TCR) through inside-out signaling, a process that is partially mediated by phosphoinositide 3-kinase (PI3K) and its product phosphatidylinositol 3,4,5-trisphosphate (PIP 3 ). To evaluate potential roles of PI3K in LFA-1 activation, we designed a library of CRISPR/single guide RNAs targeting known and potential PIP 3 -binding proteins and screened for effects on the ability of primary mouse T cells to bind to ICAM-1. We identified multiple proteins that regulated the binding of LFA-1 to ICAM-1, including the Rap1 and Ras GTPase-activating protein RASA3. We found that RASA3 suppressed LFA-1 activation in T cells, that its expression was rapidly reduced upon T cell activation, and that its activity was inhibited by PI3K. Loss of RASA3 in T cells led to increased Rap1 activation, defective lymph node entry and egress, and impaired responses to T-dependent immunization in mice. Our results reveal a critical role for RASA3 in T cell migration, homeostasis, and function.

Published
2022

35. A Multi-scale, Multiomic Atlas of Human Normal and Follicular Lymphoma Lymph Nodes

Author

Andrea J. Radtke, Ekaterina Postovalova, Arina Varlamova, Alexander Bagaev, Maria Sorokina, Olga Kudryashova, Mark Meerson, Margarita Polyakova, Ilia Galkin, Viktor Svekolkin, Sergey Isaev, Grigory Perelman, Yaroslav Lozinsky, Ziv Yaniv, Bradley C. Lowekamp, Emily Speranza, Li Yao, Stefania Pittaluga, Arthur L. Shaffer, Danny Jonigk, James D. Phelan, Theresa Davies-Hill, Da Wei Huang, Pavel Ovcharov, Krystle Nomie, Ekaterina Nuzhdina, Nikita Kotlov, Ravshan Ataullakhanov, Nathan Fowler, Michael Kelly, Jagan Muppidi, Jeremy Davis, Jonathan M. Hernandez, Wyndham H. Wilson, Elaine S. Jaffe, Louis M. Staudt, Mark Roschewski, and Ronald N. Germain

Subjects
History, Polymers and Plastics, Business and International Management, Industrial and Manufacturing Engineering
Abstract

SUMMARYReference atlases, molecular and spatial maps of mammalian tissues, are critical resources for discovery efforts and translational research. Their utility is dependent on operationalizing the resulting data by identifying cell types, histological patterns, and predictive biomarkers underlying health and disease. The human lymph node (LN) offers a compelling use case because of its importance in immunity, structural and cellular diversity, and neoplastic involvement. One hematological malignancy, follicular lymphoma (FL), evolves from developmentally blocked germinal center B cells residing in and trafficking through these tissues. To promote survival and immune escape, tumor B cells undergo significant genetic changes and extensively remodel the lymphoid microenvironment. Here, we present an integrated portrait of healthy and FL LNs using multiple genomic and advanced imaging technologies. By leveraging the strengths of each platform, we identified several tumor-specific features and microenvironmental patterns enriched in individuals who experience early relapse, the most high-risk of FL patients.

Published
2022

36. The Role of Canonical Transient Receptor Potential Channels in Seizure and Excitotoxicity

Author

Fang Zheng and Kevin D. Phelan

Subjects
canonical transient receptor potential channels, metabotropic glutamate receptors, epileptiform burst firing, seizure, excitotoxicity, Cytology, QH573-671
Abstract

Canonical transient receptor potential (TRPC) channels are a family of polymodal cation channels with some degree of Ca2+ permeability. Although initially thought to be channels mediating store-operated Ca2+ influx, TRPC channels can be activated by stimulation of Gq-coupled G-protein coupled receptors, or by an increase in intracellular free Ca2+ concentration. Thus, activation of TRPC channels could be a common downstream event of many signaling pathways that contribute to seizure and excitotoxicity, such as N-methyl-D-aspartate (NMDA) receptor-mediated Ca2+ influx, or metabotropic glutamate receptor activation. Recent studies with genetic ablation of various TRPC family members have demonstrated that TRPC channels, in particular heteromeric TRPC1/4 channels and homomeric TRPC5 channels, play a critical role in both pilocarpine-induced acute seizures and neuronal cell death. However, exact underlying mechanisms remain to be fully elucidated, and selective TRPC modulators and antibodies with better specificity are urgently needed for future research.

Published
2014
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38. Ethanol modulation of cerebellar neuroinflammation in a postnatal mouse model of fetal alcohol spectrum disorders

Author

Paul D. Drew, Ania K. Majewska, Kevin D. Phelan, Jennifer W. Johnson, James C. Douglas, Tonya M. Rafferty, Cynthia J.M. Kane, and Victoria M. Niedzwiedz-Massey

Subjects
0301 basic medicine, Cerebellum, Inflammasomes, NOS1, Gene Expression, Neuropathology, Article, Sholl analysis, Mice, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Pregnancy, medicine, Animals, Receptor, Neuroinflammation, Microglia, Chemokine CX3CL1, business.industry, Granule cell, Mice, Inbred C57BL, 030104 developmental biology, medicine.anatomical_structure, Fetal Alcohol Spectrum Disorders, Neuroinflammatory Diseases, Cytokines, Female, business, Neuroscience, 030217 neurology & neurosurgery
Abstract

Fetal alcohol spectrum disorders (FASD) are alarmingly common, result in significant personal and societal loss, and there is no effective treatment for these disorders. Cerebellar neuropathology is common in FASD and causes aberrant cognitive and motor function. Ethanol induced neuroinflammation is believed to contribute to neuropathological sequelae of FASD, and was previously demonstrated in the cerebellum in animal models of FASD. We now demonstrate neuroinflammation persists in the cerebellum several days following cessation of ethanol treatment in an early postnatal mouse model, with meaningful implications for timing of therapeutic intervention in FASD. We also demonstrate by Sholl analysis that ethanol decreases ramification of microglia cell processes in cells located near the Purkinje cell layer but not those near the external granule cell layer. Ethanol did not alter the expression of anti-inflammatory molecules or molecules that constitute NLRP1 and NLRP3 inflammasomes. Interestingly, ethanol decreased the expression of IL-23a (P19) and IL-12Rβ1 suggesting that ethanol may suppress IL-12 and IL-23 signaling. Fractalkine-fractalkine receptor (CX3CL1-CX3CR1) signaling is believed to suppress microglial activation and our demonstration that ethanol decreases CX3CL1 expression suggests that ethanol modulation of CX3CL1-CX3CR1 signaling may contribute to cerebellar neuroinflammation and neuropathology. We demonstrate ethanol alters the expression of specific molecules in the cerebellum understudied in FASD, but crucial for immune responses. Ethanol increases the expression of NOX-2 and NGP and decreases the expression of RAG1, NOS1, CD59a, S1PR5, PTPN22, GPR37, and Serpinb1b. These molecules represent a new horizon as potential targets for development of FASD therapy.

Published
2021

39. Phase 1 Study of Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, and Lenalidomide in Combination with Polatuzumab (ViPOR-P) in Relapsed/Refractory B-Cell Lymphoma: Preliminary Analysis of Safety and Efficacy

Author

Christopher Melani, Rahul Lakhotia, Stefania Pittaluga, James D. Phelan, Jillian Simard, Jagan R. Muppidi, Craig J. Thomas, Michele Ceribelli, Frances Anne Tosto, Amynah Pradhan, Anna Marie Juanitez, Seth M. Steinberg, Elaine S. Jaffe, Mark Roschewski, Louis M. Staudt, and Wyndham H. Wilson

Subjects
Immunology, Cell Biology, Hematology, Biochemistry
Published
2022

40. Active and passive defects in tetragonal tungsten bronze relaxor ferroelectrics

Author

Bi-Xia Wang, M J Krogstad, H Zheng, R Osborn, S Rosenkranz, and D Phelan

Subjects
General Materials Science, Condensed Matter Physics
Abstract

Tetragonal tungsten bronze (TTB) based oxides constitute a large family of dielectric materials which are known to exhibit complex distortions producing incommensurately modulated superstructures as well as significant local deviations from their average symmetry. The local deviations produce diffuse scattering in diffraction experiments. The structure as well as the charge dynamics of these materials are anticipated to be sensitive to defects, such as cation or oxygen vacancies. In this work, in an effort to understand how the structural and charge dynamical properties respond to these two types of vacancy defects, we have performed measurements of dielectric susceptibilities and single crystal diffraction experiments of two types of TTB materials with both ‘filled’ (Ba2NdFeNb4O15 and Ba2PrFeNb4O15) and ‘unfilled’ (Sr0.5Ba0.5Nb2O6) cation sublattices. We also perform these measurements before and after oxygen annealing, which alters the oxygen vacancy concentrations. Surprisingly, we find that many of the diffuse scattering features that are present in the unfilled structure are also present in the filled structure, suggesting that the random fields and disorder that are characteristic of the unfilled structure are not responsible for many of the local structural features that are reflected in the diffuse scattering. Oxygen annealing clearly affected both color and dielectric properties, consistent with a diminishment of the oxygen vacancy concentration, but had little effect on observed diffuse patterns.

Published
2022

41. Molecular Classification and Treatment of Diffuse Large B-Cell Lymphoma and Primary Mediastinal B-Cell Lymphoma

Author

Wyndham H. Wilson, James D. Phelan, and Mark Roschewski

Subjects
0301 basic medicine, Cancer Research, Immunoconjugates, medicine.medical_treatment, Clinical Decision-Making, Immunotherapy, Adoptive, Mediastinal Neoplasms, Article, Disease-Free Survival, 03 medical and health sciences, 0302 clinical medicine, immune system diseases, hemic and lymphatic diseases, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, Molecular Targeted Therapy, Progression-free survival, Immune Checkpoint Inhibitors, Clinical Trials as Topic, Chemotherapy, Receptors, Chimeric Antigen, Genetic heterogeneity, business.industry, Immunotherapy, medicine.disease, Progression-Free Survival, Chimeric antigen receptor, Lymphoma, 030104 developmental biology, Oncology, Drug Resistance, Neoplasm, 030220 oncology & carcinogenesis, Cancer research, Lymphoma, Large B-Cell, Diffuse, Primary mediastinal B-cell lymphoma, Neoplasm Recurrence, Local, business, Diffuse large B-cell lymphoma
Abstract

Diffuse large B-cell lymphoma (DLBCL) encompasses a group of aggressive B-cell non-Hodgkin lymphomas with striking genetic heterogeneity and variable clinical presentations. Among these is primary mediastinal B-cell lymphoma (PMBL), which has unique clinical and molecular features resembling Hodgkin lymphoma. Treatment of DLBCL is usually curative, but identifiable subsets at highest risk for treatment failure may benefit from intensified chemotherapy regimens and/or targeted agents added to frontline therapy. Recent comprehensive genomic analyses have identified distinct genetic subtypes of DLBCL with characteristic genetic drivers and signaling pathways that are targetable. Immune therapy with chimeric antigen receptor T cells and checkpoint inhibitors has revolutionized the treatment of relapsed or refractory disease, and antibody drug conjugates have weaponized otherwise intolerable cytotoxic agents. Ongoing clinical trials are further refining the specificity of these approaches in different genetic subtypes and moving them from the setting of recurrent disease to frontline treatment in high-risk patient populations.

Published
2020

42. Oncogenic RAS commandeers amino acid sensing machinery to aberrantly activate mTORC1 in multiple myeloma

Author

Frances A. Tosto, Ping Chen, Dickran Kazandjian, Craig J. Thomas, George E. Wright, Kelli M. Wilson, Thomas Oellerich, James W. Lord, Carleen Klumpp-Thomas, Irina Maric, Grace Smith, Crystal McKnight, Da-Wei Huang, Jan Wisnieski, Xin Yu, Ryan M. Young, Björn Häupl, Michele Ceribelli, Arnold Bolomsky, James Q. Wang, Erin S Beck, Callie K. Van Winkle, Jameson Travers, James D. Phelan, Stefania Pittaluga, and Yandan Yang

Subjects
Gene isoform, chemistry.chemical_classification, MAPK/ERK pathway, Mitogen-Activated Protein Kinase Kinases, Multidisciplinary, Chemistry, Mutant, General Physics and Astronomy, mTORC1, General Chemistry, Mechanistic Target of Rapamycin Complex 1, General Biochemistry, Genetics and Molecular Biology, Amino acid, Genes, ras, Mutation, Cancer research, Humans, Protein Isoforms, Amino acid transporter, Amino Acids, Multiple Myeloma, Gene, PI3K/AKT/mTOR pathway, Transcription Factors
Abstract

Oncogenic mutations within the RAS pathway are common in multiple myeloma (MM), an incurable malignancy of plasma cells. However, the mechanisms of pathogenic RAS signaling in this disease remain enigmatic and difficult to inhibit therapeutically. We employed an unbiased proteogenomic approach to dissect RAS signaling in MM by combining genome-wide CRISPR-Cas9 screening with quantitative mass spectrometry focused on RAS biology. We discovered that mutant isoforms of RAS organized a signaling complex with the amino acid transporter, SLC3A2, and MTOR on endolysosomes, which directly activated mTORC1 by co-opting amino acid sensing pathways. MM tumors with high expression of mTORC1-dependent genes were more aggressive and enriched in RAS mutations, and we detected interactions between RAS and MTOR in MM patient tumors harboring mutant RAS isoforms. Inhibition of RAS-dependent mTORC1 activity synergized with MEK and ERK inhibitors to quench pathogenic RAS signaling in MM cells. This study redefines the RAS pathway in MM and provides a mechanistic and rational basis to target this novel mode of RAS signaling.

Published
2022

43. Overcoming Acquired Epigenetic Resistance to BTK Inhibitors

Author

Michael C. Kelly, Xiaohu Zhang, Kelli M. Wilson, Erika M Gaglione, Inhye E. Ahn, Zachary Rae, Lu Chen, Louis M. Staudt, Weihong Xu, Yandan Yang, James D. Phelan, Sandrine Roulland, Dan E. Webster, Arthur L. Shaffer, Björn Häupl, Hong Zhao, Xin Yu, Clare Sun, George E. Wright, Jaewoo Choi, Crystal McKnight, Da-Wei Huang, Craig J. Thomas, Ryan M. Young, Monica Kasbekar, James Q. Wang, Thomas Oellerich, Wyndham H. Wilson, Carleen Klumpp-Thomas, Adrian Wiestner, and Michele Ceribelli

Subjects
biology, business.industry, Chronic lymphocytic leukemia, breakpoint cluster region, General Medicine, TCF4, medicine.disease, Lymphoma, chemistry.chemical_compound, chemistry, immune system diseases, Ibrutinib, hemic and lymphatic diseases, Cancer research, biology.protein, medicine, Bruton's tyrosine kinase, Epigenetics, business, Transcription factor, Research Articles
Abstract

The use of Bruton tyrosine kinase (BTK) inhibitors to block B-cell receptor (BCR)–dependent NF-κB activation in lymphoid malignancies has been a major clinical advance, yet acquired therapeutic resistance is a recurring problem. We modeled the development of resistance to the BTK inhibitor ibrutinib in the activated B-cell (ABC) subtype of diffuse large B-cell lymphoma, which relies on chronic active BCR signaling for survival. The primary mode of resistance was epigenetic, driven in part by the transcription factor TCF4. The resultant phenotypic shift altered BCR signaling such that the GTPase RAC2 substituted for BTK in the activation of phospholipase Cγ2, thereby sustaining NF-κB activity. The interaction of RAC2 with phospholipase Cγ2 was also increased in chronic lymphocytic leukemia cells from patients with persistent or progressive disease on BTK inhibitor treatment. We identified clinically available drugs that can treat epigenetic ibrutinib resistance, suggesting combination therapeutic strategies. Significance: In diffuse large B-cell lymphoma, we show that primary resistance to BTK inhibitors is due to epigenetic rather than genetic changes that circumvent the BTK blockade. We also observed this resistance mechanism in chronic lymphocytic leukemia, suggesting that epigenetic alterations may contribute more to BTK inhibitor resistance than currently thought. See related commentary by Pasqualucci, p. 555. This article is highlighted in the In This Issue feature, p. 549

Published
2021

44. In vivo CRISPR screens reveal a HIF-1α-mTOR-network regulates T follicular helper versus Th1 cells

Author

Bonnie Huang, James D. Phelan, Silvia Preite, Julio Gomez-Rodriguez, Kristoffer H. Johansen, Hirofumi Shibata, Arthur L. Shaffer, Qin Xu, Brendan Jeffrey, Martha Kirby, Stacie Anderson, Yandan Yang, Selamawit Gossa, Dorian B. McGavern, Louis M. Staudt, and Pamela L. Schwartzberg

Subjects
Multidisciplinary, Science, TOR Serine-Threonine Kinases, General Physics and Astronomy, Gene Expression, Cell Differentiation, General Chemistry, T-Lymphocytes, Helper-Inducer, Mechanistic Target of Rapamycin Complex 1, Th1 Cells, Germinal Center, Hypoxia-Inducible Factor 1, alpha Subunit, General Biochemistry, Genetics and Molecular Biology, Immunity, Humoral, Gene Knockout Techniques, Mice, Virus Diseases, Antibody Formation, Animals, Clustered Regularly Interspaced Short Palindromic Repeats, Glycolysis
Abstract

T follicular helper (Tfh) cells provide signals to initiate and maintain the germinal center (GC) reaction and are crucial for the generation of robust, long-lived antibody responses, but how the GC microenvironment affects Tfh cells is not well understood. Here we develop an in vivo T cell-intrinsic CRISPR-knockout screen to evaluate Tfh and Th1 cells in an acute viral infection model to identify regulators of Tfh cells in their physiological setting. Using a screen of druggable-targets, alongside genetic, transcriptomic and cellular analyses, we identify a function of HIF-1α in suppressing mTORC1-mediated and Myc-related pathways, and provide evidence that VHL-mediated degradation of HIF-1α is required for Tfh development; an expanded in vivo CRISPR screen reveals multiple components of these pathways that regulate Tfh versus Th1 cells, including signaling molecules, cell-cycle regulators, nutrient transporters, metabolic enzymes and autophagy mediators. Collectively, our data serve as a resource for studying Tfh versus Th1 decisions, and implicate the VHL-HIF-1α axis in fine-tuning Tfh generation.

Published
2021

45. Synthesis and characterization of bulk Nd

Author

Bi-Xia, Wang, Hong, Zheng, E, Krivyakina, O, Chmaissem, Pietro Papa, Lopes, J W, Lynn, Leighanne C, Gallington, Y, Ren, S, Rosenkranz, J F, Mitchell, and D, Phelan

Subjects
Article
Abstract

The recent reports of superconductivity in Nd(1–x)Sr(x)NiO(2)/SrTiO(3) heterostructures have reinvigorated interest in potential superconductivity of low-oxidation state nickelates. Synthesis of Ni(1+)-containing compounds is notoriously difficult. In the current work, a combined sol-gel combustion and high-pressure annealing technique was employed to prepare polycrystalline perovskite Nd(1–x)Sr(x)NiO(3) (x = 0, 0.1, and 0.2). Metal nitrates and metal acetates were used as starting materials, and the latter were found to be superior to the former in terms of safety and reactivity. The Nd(1–x)Sr(x)NiO(3) compounds were subsequently reduced to Nd(1–x)Sr(x)NiO(2) using calcium hydride in a sealed, evacuated quartz tube. To understand the synthesis pathway, the evolution from NdNiO(3) to NdNiO(2) was monitored using in situ synchrotron x-ray diffraction during the reduction process. Electrical transport properties were consistent with an insulator-metal transition occurring between x = 0 and 0.1 for Nd(1–x)Sr(x)NiO(3). Superconductivity was not observed in our bulk samples of Nd(1–x)Sr(x)NiO(2). Neutron diffraction experiments at 3 and 300 K were performed on Nd(0.9)Sr(0.1)NiO(2), in which no magnetic Bragg reflections were observed, and the results of structural Rietveld refinement are provided.

Published
2021

46. Fluctuation-induced interactions and the spin-glass transition inFe2TiO5

Author

Theo Siegrist, Sergey Syzranov, Arthur P. Ramirez, D. Phelan, Tiglet Besara, Yan Xin, P. G. LaBarre, S. Rosenkranz, and Feng Ye

Subjects
Materials science, Spin glass, Strongly Correlated Electrons (cond-mat.str-el), Condensed matter physics, Spins, Transition temperature, FOS: Physical sciences, Disordered Systems and Neural Networks (cond-mat.dis-nn), 02 engineering and technology, Condensed Matter - Disordered Systems and Neural Networks, Neutron scattering, 021001 nanoscience & nanotechnology, 01 natural sciences, Condensed Matter - Strongly Correlated Electrons, Magnetization, symbols.namesake, 0103 physical sciences, symbols, Antiferromagnetism, Condensed Matter::Strongly Correlated Electrons, van der Waals force, 010306 general physics, 0210 nano-technology, Glass transition
Abstract

We investigate the spin-glass transition in the strongly frustrated well-known compound $Fe_2TiO_5$. A remarkable feature of this transition, widely discussed in the literature, is its anisotropic properties: the transition manifests itself in the magnetic susceptibly only along one axis, despite $Fe^{3+}$ $d^5$ spins having no orbital component. We demonstrate, using neutron scattering, that below the transition temperature $T_g = 55 K$, $Fe_2TiO_5$ develops nanoscale surfboard shaped antiferromagnetic regions in which the $Fe^{3+}$ spins are aligned perpendicular to the axis which exhibits freezing. We show that the glass transition may result from the freezing of transverse fluctuations of the magnetization of these regions and we develop a mean-field replica theory of such a transition, revealing a type of magnetic van der Waals effect., 14 pages, 4 figures, 6 page supplemental material, 2 figures

Published
2021

47. TARGETING PROXIMAL BCR SIGNALING PATHWAY IN DIFFUSE LARGE B‐CELL LYMPHOMA

Author

Thomas Oellerich, J. W Choi, Arthur L. Shaffer, S Scheich, Youwen Yang, James D. Phelan, Craig J. Thomas, X. Yu, Björ Häupl, George Wright, S Corcoran, B Wang, Michele Ceribelli, D. W Huang, and L. M. Staudt

Subjects
Cancer Research, Oncology, medicine, Cancer research, Hematology, General Medicine, BCR Signaling Pathway, Biology, medicine.disease, Diffuse large B-cell lymphoma
Published
2021

48. An innovative technique to promote understanding of anatomy for nurse practitioner students

Author

Leonie DeClerk, Teresa Whited, Kevin D. Phelan, and Albrey Berber

Subjects
Modalities, 030504 nursing, business.industry, education, MEDLINE, General Medicine, Anatomy, Human body, Comparative anatomy, 03 medical and health sciences, Dissection, 0302 clinical medicine, Doctor of Nursing Practice, Health care, 030212 general & internal medicine, Thematic analysis, 0305 other medical science, Psychology, business, General Nursing
Abstract

Nurse practitioner (NP) students are required to have a clear understanding of the complexities of the human body. Students enter graduate studies with varying experiences and backgrounds in anatomy and physiology. Evidence suggests that human anatomy laboratories increase learning outcomes when compared with comparative anatomy modalities. The purpose of this evaluation was to determine if teaching with a computed tomography (CT)-based three-dimensional (3D) anatomy table and cadaveric specimens improves Doctor of Nursing Practice (DNP) and NP students' understanding of anatomy in health assessment. Students participated in a hands-on anatomy review using a 3D anatomy table and human cadavers to master the five included body systems. Presurveys and postsurveys were administered to determine how much time had lapsed since our students' most recent anatomy class and the type of dissection laboratory provided within that class; to assess knowledge confidence in pediatric Head, Eyes, Ears, Nose and Throat (HEENT) anatomy; and to assess students' confidence in pediatric anatomical knowledge for all five body systems. Data were analyzed using a Mann-Whitney U test with independent samples. All areas with the exception of HEENT showed clinically significant improvement, including overall scores. Many positive themes were identified using qualitative thematic analysis. Teaching with a CT-based, 3D anatomy table with cadaveric specimens improved DNP and NP students' confidence levels in pediatric anatomy knowledge for all five systems. This innovative combination of human cadavers and virtual technology has the potential to produce advanced anatomical understanding for prospective health care professionals and to validate their capacity to conduct complex health assessments and procedures.

Published
2019

49. Pathogenic B‐cell receptor signaling in lymphoid malignancies: New insights to improve treatment

Author

Wyndham H. Wilson, Louis M. Staudt, Ryan M. Young, and James D. Phelan

Subjects
0301 basic medicine, Lymphoma, Immunology, B-cell receptor, Receptors, Antigen, B-Cell, Disease, Biology, Autoantigens, Article, 03 medical and health sciences, 0302 clinical medicine, immune system diseases, hemic and lymphatic diseases, medicine, Animals, Humans, Immunology and Allergy, Receptor, breakpoint cluster region, TLR9, Cancer, Germinal Center, medicine.disease, Leukemia, Lymphoid, Cell Transformation, Neoplastic, 030104 developmental biology, Cancer research, Signal transduction, Signal Transduction, 030215 immunology
Abstract

Signals emanating from the B cell receptor (BCR) promote proliferation and survival in diverse forms of B cell lymphoma. Precision medicine strategies targeting the BCR pathway have been generally effective in treating lymphoma, but often fail to produce durable responses in diffuse large B cell lymphoma (DLBCL), a common and aggressive cancer. New insights into DLBCL biology garnered from genomic analyses and functional proteogenomic studies have identified novel modes of BCR signaling in this disease. Herein, we describe the distinct roles of antigen-dependent and antigen-independent BCR signaling in different subtypes of DLBCL. We highlight mechanisms by which the BCR cooperates with TLR9 and mutant isoforms of MYD88 to drive sustained NF-κB activity in the activated B cell-like (ABC) subtype of DLBCL. Finally, we discuss progress in detecting and targeting oncogenic BCR signaling to improve the survival of patients with lymphoma.

Published
2019

50. The melanocortin pathway and control of appetite-progress and therapeutic implications

Author

Kevin D. Phelan and Giulia Baldini

Subjects
endocrine system, medicine.medical_specialty, Pro-Opiomelanocortin, Endocrinology, Diabetes and Metabolism, Appetite, Neuropeptide, Biology, Article, Energy homeostasis, Mice, Endocrinology, Orexigenic, Internal medicine, medicine, Animals, Humans, Obesity, Neurons, integumentary system, Leptin, digestive, oral, and skin physiology, Neuropeptide Y receptor, Melanocortins, nervous system, alpha-MSH, Hypothalamus, Receptor, Melanocortin, Type 4, Ghrelin, Anti-Obesity Agents, Melanocortin, Peptides, hormones, hormone substitutes, and hormone antagonists, Paraventricular Hypothalamic Nucleus, Signal Transduction, medicine.drug
Abstract

The initial discovery that ob/ob mice become obese because of a recessive mutation of the leptin gene has been crucial to discover the melanocortin pathway to control appetite. In the melanocortin pathway, the fed state is signaled by abundance of circulating hormones such as leptin and insulin, which bind to receptors expressed at the surface of pro-opiomelanocortin (POMC) neurons to promote processing of POMC to the mature hormone α-melanocyte-stimulating hormone (α-MSH). The α-MSH released by POMC neurons then signals to decrease energy intake by binding to melanocortin-4 receptor (MC4R) expressed by MC4R neurons to the paraventricular nucleus (PVN). Conversely, in the ‘starved state’ activity of agouti-related neuropeptide (AgRP) and of neuropeptide Y (NPY)-expressing neurons is increased by decreased levels of circulating leptin and insulin and by the orexigenic hormone ghrelin to promote food intake. This initial understanding of the melanocortin pathway has recently been implemented by the description of the complex neuronal circuit that controls the activity of POMC, AgRP/NPY and MC4R neurons and downstream signaling by these neurons. This review summarizes the progress done on the melanocortin pathway and describes how obesity alters this pathway to disrupt energy homeostasis. We also describe progress on how leptin and insulin receptors signal in POMC neurons, how MC4R signals and how altered expression and traffic of MC4R change the acute signaling and desensitization properties of the receptor. We also describe how the discovery of the melanocortin pathway has led to the use of melanocortin agonists to treat obesity derived from genetic disorders.

Published
2019

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