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5. Inhibition of BTK and PI3Kδ impairs the development of human JMML stem and progenitor cells

Author

Ramdas, Baskar, Yuen, Lisa Deng, Palam, Lakshmi Reddy, Patel, Roshini, Pasupuleti, Santhosh Kumar, Jideonwo, Victoria, Zhang, Ji, Maguire, Callista, Wong, Eric, Kanumuri, Rahul, Zhang, Chujing, Sandusky, George, Chan, Rebecca J, Zhang, Chi, Stieglitz, Elliot, Haneline, Laura, and Kapur, Reuben

Subjects
Biochemistry and Cell Biology, Biomedical and Clinical Sciences, Biological Sciences, Cancer, Stem Cell Research, Stem Cell Research - Nonembryonic - Non-Human, Pediatric, Childhood Leukemia, Stem Cell Research - Nonembryonic - Human, Pediatric Research Initiative, Pediatric Cancer, Hematology, Rare Diseases, Genetics, Clinical Research, Aetiology, 2.1 Biological and endogenous factors, Agammaglobulinaemia Tyrosine Kinase, Animals, Humans, Leukemia, Myelomonocytic, Juvenile, Mice, Phosphatidylinositol 3-Kinases, Proto-Oncogene Proteins c-akt, Splenomegaly, Stem Cells, Thrombocytopenia, BTK, JMML, PI3K-p110δ, Thromobocytopenia, anemia, leukemia, monocytosis, Technology, Medical and Health Sciences, Biotechnology, Clinical sciences, Medical biotechnology
Abstract

Juvenile myelomonocytic leukemia (JMML) is an aggressive myeloproliferative neoplasia that lacks effective targeted chemotherapies. Clinically, JMML manifests as monocytic leukocytosis, splenomegaly with consequential thrombocytopenia. Most commonly, patients have gain-of-function (GOF) oncogenic mutations in PTPN11 (SHP2), leading to Erk and Akt hyperactivation. Mechanism(s) involved in co-regulation of Erk and Akt in the context of GOF SHP2 are poorly understood. Here, we show that Bruton's tyrosine kinase (BTK) is hyperphosphorylated in GOF Shp2-bearing cells and utilizes B cell adaptor for PI3K to cooperate with p110δ, the catalytic subunit of PI3K. Dual inhibition of BTK and p110δ reduces the activation of both Erk and Akt. In vivo, individual targeting of BTK or p110δ in a mouse model of human JMML equally reduces monocytosis and splenomegaly; however, the combined treatment results in a more robust inhibition and uniquely rescues anemia and thrombocytopenia. RNA-seq analysis of drug-treated mice showed a profound reduction in the expression of genes associated with leukemic cell migration and inflammation, leading to correction in the infiltration of leukemic cells in the lung, liver, and spleen. Remarkably, in a patient derived xenograft model of JMML, leukemia-initiating stem and progenitor cells were potently inhibited in response to the dual drug treatment.

Published
2022

10. Obesity-induced inflammation exacerbates clonal hematopoiesis

Author

Pasupuleti, Santhosh Kumar, Ramdas, Baskar, Burns, Sarah S., Palam, Lakshmi Reddy, Kanumuri, Rahul, Kumar, Ramesh, Pandhiri, Taruni Reddy, Dave, Utpal P., Yellapu, Nanda Kumar, Zhou, Xinyu, Zhang, Chi, Sandusky, George E., Yu, Zhi, Honigberg, Michael C., Bick, Alexander G., Griffin, Gabriel K., Niroula, Abhishek, Ebert, Benjamin L., Paczesny, Sophie, Natarajan, Pradeep, and Kapur, Reuben

Subjects
Obesity -- Complications and side effects, Hematopoiesis -- Health aspects -- Genetic aspects, Leukemia -- Risk factors -- Development and progression, Lymphomas -- Risk factors -- Development and progression, Multiple myeloma -- Risk factors -- Development and progression, Health care industry
Abstract

Characterized by the accumulation of somatic mutations in blood cell lineages, clonal hematopoiesis of indeterminate potential (CHIP) is frequent in aging and involves the expansion of mutated hematopoietic stem and progenitor cells (HSC/Ps) that leads to an increased risk of hematologic malignancy. However, the risk factors that contribute to CHIP-associated clonal hematopoiesis (CH) are poorly understood. Obesity induces a proinflammatory state and fatty bone marrow (FBM), which may influence CHIP-associated pathologies. We analyzed exome sequencing and clinical data for 47,466 individuals with validated CHIP in the UK Biobank. CHIP was present in 5.8% of the study population and was associated with a significant increase in the waist-to-hip ratio (WHR). Mouse models of obesity and CHIP driven by heterozygosity of Tet2, Dnmt3a, Asxl1, and Jak2 resulted in exacerbated expansion of mutant HSC/Ps due in part to excessive inflammation. Our results show that obesity is highly associated with CHIP and that a proinflammatory state could potentiate the progression of CHIP to more significant hematologic neoplasia. The calcium channel blockers nifedipine and SKF-96365, either alone or in combination with metformin, MCC950, or anakinra (IL-1 receptor antagonist), suppressed the growth of mutant CHIP cells and partially restored normal hematopoiesis. Targeting CHIP-mutant cells with these drugs could be a potential therapeutic approach to treat CH and its associated abnormalities in individuals with obesity., Introduction Clonal hematopoiesis of indeterminate potential (CHIP) is a newly-discovered condition that increases the risk of all-cause mortality and the development of hematologic malignancies (1, 2). The prevalence of CHIP [...]

Published
2023
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11. Toll-like receptor 3 (TLR3) promotes the resolution of Chlamydia muridarum genital tract infection in congenic C57BL/6N mice.

Author

Carrasco, Sebastian, Hu, Sishun, Imai, Denise, Kumar, Ramesh, Sandusky, George, Yang, X, and Derbigny, Wilbert

Subjects
Animals, Chlamydia Infections, Chlamydia muridarum, Cytokines, Disease Susceptibility, Female, Mice, Mice, Inbred C57BL, Mice, Knockout, Reproductive Tract Infections, T-Lymphocyte Subsets, Toll-Like Receptor 3
Abstract

Chlamydia trachomatis urogenital serovars primarily replicate in epithelial cells lining the reproductive tract. Epithelial cells recognize Chlamydia through cell surface and cytosolic receptors, and/or endosomal innate receptors such as Toll-like receptors (TLRs). Activation of these receptors triggers both innate and adaptive immune mechanisms that are required for chlamydial clearance, but are also responsible for the immunopathology in the reproductive tract. We previously demonstrated that Chlamydia muridarum (Cm) induces IFN-β in oviduct epithelial cells (OE) in a TLR3-dependent manner, and that the synthesis of several cytokines and chemokines are diminished in Cm-challenged OE derived from TLR3-/- 129S1 mice. Furthermore, our in vitro studies showed that Cm replication in TLR3-/- OE is more efficient than in wild-type OE. Because TLR3 modulates the release inflammatory mediators involved in host defense during Cm infection, we hypothesized that TLR3 plays a protective role against Cm-induced genital tract pathology in congenic C57BL/6N mice. Using the Cm mouse model for human Chlamydia genital tract infections, we demonstrated that TLR3-/- mice had increased Cm shedding during early and mid-stage genital infection. In early stage infection, TLR3-/- mice showed a diminished synthesis of IFN-β, IL-1β, and IL-6, but enhanced production of IL-10, TNF-α, and IFN-γ. In mid-stage infection, TLR3-/- mice exhibited significantly enhanced lymphocytic endometritis and salpingitis than wild-type mice. These lymphocytes were predominantly scattered along the endometrial stroma and the associated smooth muscle, and the lamina propria supporting the oviducts. Surprisingly, our data show that CD4+ T-cells are significantly enhanced in the genital tract TLR3-/- mice during mid-stage Chlamydial infection. In late-stage infections, both mouse strains developed hydrosalpinx; however, the extent of hydrosalpinx was more severe in TLR3-/- mice. Together, these data suggest that TLR3 promotes the clearance of Cm during early and mid-stages of genital tract infection, and that loss of TLR3 is detrimental in the development hydrosalpinx.

Published
2018

12. Integrated genomic and molecular characterization of cervical cancer

Author

Burk, Robert D, Chen, Zigui, Saller, Charles, Tarvin, Katherine, Carvalho, Andre L, Scapulatempo-Neto, Cristovam, Silveira, Henrique C, Fregnani, José H, Creighton, Chad J, Anderson, Matthew L, Castro, Patricia, Wang, Sophia S, Yau, Christina, Benz, Christopher, Robertson, A Gordon, Mungall, Karen, Lim, Lynette, Bowlby, Reanne, Sadeghi, Sara, Brooks, Denise, Sipahimalani, Payal, Mar, Richard, Ally, Adrian, Clarke, Amanda, Mungall, Andrew J, Tam, Angela, Lee, Darlene, Chuah, Eric, Schein, Jacqueline E, Tse, Kane, Kasaian, Katayoon, Ma, Yussanne, Marra, Marco A, Mayo, Michael, Balasundaram, Miruna, Thiessen, Nina, Dhalla, Noreen, Carlsen, Rebecca, Moore, Richard A, Holt, Robert A, Jones, Steven JM, Wong, Tina, Pantazi, Angeliki, Parfenov, Michael, Kucherlapati, Raju, Hadjipanayis, Angela, Seidman, Jonathan, Kucherlapati, Melanie, Ren, Xiaojia, Xu, Andrew W, Yang, Lixing, Park, Peter J, Lee, Semin, Rabeno, Brenda, Huelsenbeck-Dill, Lori, Borowsky, Mark, Cadungog, Mark, Iacocca, Mary, Petrelli, Nicholas, Swanson, Patricia, Ojesina, Akinyemi I, Le, Xuan, Sandusky, George, Adebamowo, Sally N, Akeredolu, Teniola, Adebamowo, Clement, Reynolds, Sheila M, Shmulevich, Ilya, Shelton, Candace, Crain, Daniel, Mallery, David, Curley, Erin, Gardner, Johanna, Penny, Robert, Morris, Scott, Shelton, Troy, Liu, Jia, Lolla, Laxmi, Chudamani, Sudha, Wu, Ye, Birrer, Michael, McLellan, Michael D, Bailey, Matthew H, Miller, Christopher A, Wyczalkowski, Matthew A, Fulton, Robert S, Fronick, Catrina C, Lu, Charles, Mardis, Elaine R, Appelbaum, Elizabeth L, Schmidt, Heather K, Fulton, Lucinda A, Cordes, Matthew G, Li, Tiandao, Ding, Li, Wilson, Richard K, Rader, Janet S, Behmaram, Behnaz, Uyar, Denise, and Bradley, William

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Immunology, Women's Health, Biotechnology, Human Genome, Cervical Cancer, Infectious Diseases, Cancer, Genetics, Cancer Genomics, Sexually Transmitted Infections, 2.1 Biological and endogenous factors, 4.1 Discovery and preclinical testing of markers and technologies, APOBEC-1 Deaminase, Adenocarcinoma, B7-H1 Antigen, Carcinoma, Squamous Cell, Caspase 8, DNA-Binding Proteins, Female, Genomics, HLA-A Antigens, Human papillomavirus 16, Humans, Keratins, Mitogen-Activated Protein Kinase Kinases, Molecular Targeted Therapy, Mutation, Nuclear Proteins, PTEN Phosphohydrolase, Phosphatidylinositol 3-Kinases, Programmed Cell Death 1 Ligand 2 Protein, Protein Serine-Threonine Kinases, Proteomics, Proto-Oncogene Proteins p21(ras), RNA, Long Noncoding, Receptor, ErbB-3, Receptor, Transforming Growth Factor-beta Type II, Receptors, Transforming Growth Factor beta, Signal Transduction, Transcription Factors, Uterine Cervical Neoplasms, Virus Integration, Cancer Genome Atlas Research Network, Albert Einstein College of Medicine, Analytical Biological Services, Barretos Cancer Hospital, Baylor College of Medicine, Beckman Research Institute of City of Hope, Buck Institute for Research on Aging, Canada's Michael Smith Genome Sciences Centre, Harvard Medical School, Helen F. Graham Cancer Center &Research Institute at Christiana Care Health Services, HudsonAlpha Institute for Biotechnology, ILSbio, LLC, Indiana University School of Medicine, Institute of Human Virology, Institute for Systems Biology, International Genomics Consortium, Leidos Biomedical, Massachusetts General Hospital, McDonnell Genome Institute at Washington University, Medical College of Wisconsin, Medical University of South Carolina, Memorial Sloan Kettering Cancer Center, Montefiore Medical Center, NantOmics, National Cancer Institute, National Hospital, Abuja, Nigeria, National Human Genome Research Institute, National Institute of Environmental Health Sciences, National Institute on Deafness &Other Communication Disorders, Ontario Tumour Bank, London Health Sciences Centre, Ontario Tumour Bank, Ontario Institute for Cancer Research, Ontario Tumour Bank, The Ottawa Hospital, Oregon Health &Science University, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, SRA International, St Joseph's Candler Health System, Eli &Edythe L. Broad Institute of Massachusetts Institute of Technology &Harvard University, Research Institute at Nationwide Children's Hospital, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, University of Bergen, University of Texas MD Anderson Cancer Center, University of Abuja Teaching Hospital, University of Alabama at Birmingham, University of California, Irvine, University of California Santa Cruz, University of Kansas Medical Center, University of Lausanne, University of New Mexico Health Sciences Center, University of North Carolina at Chapel Hill, University of Oklahoma Health Sciences Center, University of Pittsburgh, University of São Paulo, Ribeir ão Preto Medical School, University of Southern California, University of Washington, University of Wisconsin School of Medicine &Public Health, Van Andel Research Institute, Washington University in St Louis, Receptor, erbB-3, General Science & Technology
Abstract

Cervical cancer remains one of the leading causes of cancer-related deaths worldwide. Here we report the extensive molecular characterization of 228 primary cervical cancers, one of the largest comprehensive genomic studies of cervical cancer to date. We observed notable APOBEC mutagenesis patterns and identified SHKBP1, ERBB3, CASP8, HLA-A and TGFBR2 as novel significantly mutated genes in cervical cancer. We also discovered amplifications in immune targets CD274 (also known as PD-L1) and PDCD1LG2 (also known as PD-L2), and the BCAR4 long non-coding RNA, which has been associated with response to lapatinib. Integration of human papilloma virus (HPV) was observed in all HPV18-related samples and 76% of HPV16-related samples, and was associated with structural aberrations and increased target-gene expression. We identified a unique set of endometrial-like cervical cancers, comprised predominantly of HPV-negative tumours with relatively high frequencies of KRAS, ARID1A and PTEN mutations. Integrative clustering of 178 samples identified keratin-low squamous, keratin-high squamous and adenocarcinoma-rich subgroups. These molecular analyses reveal new potential therapeutic targets for cervical cancers.

Published
2017

14. Effect of Age at Time of Irradiation, Sex, Genetic Diversity, and Granulopoietic Cytokine Radiomitigation on Lifespan and Lymphoma Development in Murine H-ARS Survivors.

Author

Plett, P. Artur, Chua, Hui Lin, Wu, Tong, Sampson, Carol H., Guise, Theresa A., Wright, Laura, Pagnotti, Gabriel M., Feng, Hailin, Chin-Sinex, Helen, Pike, Francis, Cox, George N., MacVittie, Thomas J., Sandusky, George, and Orschell, Christie M.

Subjects
NATURAL history, RADIATION injuries, YOUNG adults, RADIATION exposure, RADIATION damage
Abstract

Acute, high-dose radiation exposure results in life-threatening acute radiation syndrome (ARS) and debilitating delayed effects of acute radiation exposure (DEARE). The DEARE are a set of chronic multi-organ illnesses that can result in early death due to malignancy and other diseases. Animal models have proven essential in understanding the natural history of ARS and DEARE and licensure of medical countermeasures (MCM) according to the FDA Animal Rule. Our lab has developed models of hematopoietic (H)-ARS and DEARE in inbred C57BL/6J and Jackson Diversity Outbred (JDO) mice of both sexes and various ages and have used these models to identify mechanisms of radiation damage and effective MCMs. Herein, aggregate data from studies conducted over decades in our lab, consisting of 3,250 total-body lethally irradiated C57BL/6J young adult mice and 1,188 H-ARS survivors from these studies, along with smaller datasets in C57BL/6J pediatric and geriatric mice and JDO mice, were examined for lifespan and development of thymic lymphoma in survivors up to 3 years of age. Lifespan was found to be significantly shortened in H-ARS survivors compared to age-matched nonirradiated controls in all four models. Males and females exhibited similar lifespans except in the young adult C57BL/ 6J model where males survived longer than females after 16 months of age. The incidence of thymic lymphoma was increased in H-ARS survivors from the young adult and pediatric C57BL/ 6J models. Consistent with our findings in H-ARS, geriatric mice appeared more radioresistant than other models, with a lifespan and thymic lymphoma incidence more similar to nonirradiated controls than other models. Increased levels of multiple pro-inflammatory cytokines in DEARE bone marrow and serum correlated with shortened lifespan and malignancy, consistent with other animal models and human data. Of interest, G-CSF levels in bone marrow and serum 8-11 months after irradiation were significantly increased in females. Importantly, treatment with granulopoietic cytokine MCM for radiomitigation of H-ARS did not influence the long-term survival rate or incidence of thymic lymphoma in any model. Taken together, these findings indicate that the lifespan of H-ARS survivors was significantly decreased regardless of age at time of exposure or genetic diversity, and was unaffected by earlier treatment with granulopoietic cytokines for radiomitigation of H-ARS. [ABSTRACT FROM AUTHOR]

Published
2024
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18. Table S4 from Combined CDK4/6 and ERK1/2 Inhibition Enhances Antitumor Activity in NF1-Associated Plexiform Neurofibroma

Author

Flint, Alyssa C., primary, Mitchell, Dana K., primary, Angus, Steven P., primary, Smith, Abbi E., primary, Bessler, Waylan, primary, Jiang, Li, primary, Mang, Henry, primary, Li, Xiaohong, primary, Lu, Qingbo, primary, Rodriguez, Brooke, primary, Sandusky, George E., primary, Masters, Andi R., primary, Zhang, Chi, primary, Dang, Pengtao, primary, Koenig, Jenna, primary, Johnson, Gary L., primary, Shen, Weihua, primary, Liu, Jiangang, primary, Aggarwal, Amit, primary, Donoho, Gregory P., primary, Willard, Melinda D., primary, Bhagwat, Shripad V., primary, Clapp, D. Wade, primary, and Rhodes, Steven D., primary

Published
2024
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19. Figure S8 from Combined CDK4/6 and ERK1/2 Inhibition Enhances Antitumor Activity in NF1-Associated Plexiform Neurofibroma

Author

Flint, Alyssa C., primary, Mitchell, Dana K., primary, Angus, Steven P., primary, Smith, Abbi E., primary, Bessler, Waylan, primary, Jiang, Li, primary, Mang, Henry, primary, Li, Xiaohong, primary, Lu, Qingbo, primary, Rodriguez, Brooke, primary, Sandusky, George E., primary, Masters, Andi R., primary, Zhang, Chi, primary, Dang, Pengtao, primary, Koenig, Jenna, primary, Johnson, Gary L., primary, Shen, Weihua, primary, Liu, Jiangang, primary, Aggarwal, Amit, primary, Donoho, Gregory P., primary, Willard, Melinda D., primary, Bhagwat, Shripad V., primary, Clapp, D. Wade, primary, and Rhodes, Steven D., primary

Published
2024
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20. Therapeutic targeting of the E3 ubiquitin ligase SKP2 in T-ALL

Author

Rodriguez, Sonia, Abundis, Christina, Boccalatte, Francesco, Mehrotra, Purvi, Chiang, Mark Y., Yui, Mary A., Wang, Lin, Zhang, Huajia, Zollman, Amy, Bonfim-Silva, Ricardo, Kloetgen, Andreas, Palmer, Joycelynne, Sandusky, George, Wunderlich, Mark, Kaplan, Mark H., Mulloy, James C., Marcucci, Guido, Aifantis, Iannis, Cardoso, Angelo A., and Carlesso, Nadia

Published
2020
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21. Fibrosis and Hypoxia-Inducible Factor-1α–Dependent Tumors of the Soft Tissue on Loss of Von Hippel-Lindau in Mesenchymal Progenitors

Author

Mangiavini, Laura, Merceron, Christophe, Araldi, Elisa, Khatri, Richa, Gerard-O'Riley, Rita, Wilson, Tremika L, Sandusky, George, Abadie, Jerome, Lyons, Karen M, Giaccia, Amato J, and Schipani, Ernestina

Subjects
Biomedical and Clinical Sciences, Health Sciences, Stem Cell Research, Rare Diseases, Biotechnology, Cancer, Aetiology, 2.1 Biological and endogenous factors, Animals, Basic Helix-Loop-Helix Transcription Factors, Fibrosis, Humans, Hypoxia-Inducible Factor 1, alpha Subunit, Mesenchymal Stem Cells, Mice, Mice, Inbred C57BL, Mice, Transgenic, Signal Transduction, Soft Tissue Neoplasms, Synovial Membrane, Von Hippel-Lindau Tumor Suppressor Protein, Medical and Health Sciences, Pathology, Biomedical and clinical sciences, Health sciences
Abstract

The hypoxia-inducible factor (Hif)-1α (Hif-1α) and Hif-2α (Epas1) have a critical role in both normal development and cancer. von Hippel Lindau (Vhl) protein, encoded by a tumor suppressor gene, is an E3 ubiquitin ligase that targets Hif-1α and Epas1 to the proteasome for degradation. To better understand the role of Vhl in the biology of mesenchymal cells, we analyzed mutant mice lacking Vhl in mesenchymal progenitors that give rise to the soft tissues that form and surround synovial joints. Loss of Vhl in mesenchymal progenitors of the limb bud caused severe fibrosis of the synovial joints and formation of aggressive masses with histologic features of mesenchymal tumors. Hif-1α and its downstream target connective tissue growth factor were necessary for the development of these tumors, which conversely still developed in the absence of Epas1, but at lower frequency. Human tumors of the soft tissue are a very complex and heterogeneous group of neoplasias. Our novel findings in genetically altered mice suggest that activation of the HIF signaling pathway could be an important pathogenetic event in the development and progression of at least a subset of these tumors.

Published
2015

24. Data from Signaling Pathway Alterations Driven by BRCA1 and BRCA2 Germline Mutations are Sufficient to Initiate Breast Tumorigenesis by the PIK3CAH1047R Oncogene

Author

Bhat-Nakshatri, Poornima, primary, Khatpe, Aditi S., primary, Chen, Duojiao, primary, Batic, Katie, primary, Mang, Henry, primary, Herodotou, Christopher, primary, McGuire, Patrick C., primary, Xuei, Xiaoling, primary, Erdogan, Cihat, primary, Gao, Hongyu, primary, Liu, Yunlong, primary, Sandusky, George, primary, Storniolo, Anna Maria, primary, and Nakshatri, Harikrishna, primary

Published
2024
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25. Spatial N-glycomics of the normal breast microenvironment reveals fucosylated and high-mannose N-glycan signatures related to BI-RADS density and ancestry.

Author

Rujchanarong, Denys, Spruill, Laura, Sandusky, George E, Park, Yeonhee, Mehta, Anand S, Drake, Richard R, Ford, Marvella E, Nakshatri, Harikrishna, and Angel, Peggi M

Subjects
BREAST, LOBULAR carcinoma, GENEALOGY, POST-translational modification, BREAST cancer, WHITE women
Abstract

Higher breast cancer mortality rates continue to disproportionally affect black women (BW) compared to white women (WW). This disparity is largely due to differences in tumor aggressiveness that can be related to distinct ancestry-associated breast tumor microenvironments (TMEs). Yet, characterization of the normal microenvironment (NME) in breast tissue and how they associate with breast cancer risk factors remains unknown. N-glycans, a glucose metabolism-linked post-translational modification, has not been characterized in normal breast tissue. We hypothesized that normal female breast tissue with distinct Breast Imaging and Reporting Data Systems (BI-RADS) categories have unique microenvironments based on N-glycan signatures that varies with genetic ancestries. Profiles of N-glycans were characterized in normal breast tissue from BW (n  = 20) and WW (n  = 20) at risk for breast cancer using matrix assisted laser desorption/ionization (MALDI) mass spectrometry imaging (MSI). A total of 176 N-glycans (32 core-fucosylated and 144 noncore-fucosylated) were identified in the NME. We found that certain core-fucosylated, outer-arm fucosylated and high-mannose N-glycan structures had specific intensity patterns and histological distributions in the breast NME dependent on BI-RADS densities and ancestry. Normal breast tissue from BW, and not WW, with heterogeneously dense breast densities followed high-mannose patterns as seen in invasive ductal and lobular carcinomas. Lastly, lifestyles factors (e.g. age, menopausal status, Gail score, BMI, BI-RADS) differentially associated with fucosylated and high-mannose N-glycans based on ancestry. This study aims to decipher the molecular signatures in the breast NME from distinct ancestries towards improving the overall disparities in breast cancer burden. [ABSTRACT FROM AUTHOR]

Published
2024
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26. Signaling Pathway Alterations Driven by BRCA1 and BRCA2 Germline Mutations are Sufficient to Initiate Breast Tumorigenesis by the PIK3CAH1047R Oncogene

Author

Bhat-Nakshatri, Poornima, primary, Khatpe, Aditi S, additional, Chen, Duojiao, additional, Batic, Katie, additional, Mang, Henry, additional, Herodotou, Christopher, additional, McGuire, Patrick C, additional, Xuei, Xiaoling, additional, Erdogan, Cihat, additional, Gao, Hongyu, additional, Liu, Yunlong, additional, Sandusky, George E., additional, Storniolo, Anna Maria, additional, and Nakshatri, Harikrishna, additional

Published
2023
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28. Integrated Molecular Characterization of Testicular Germ Cell Tumors

Author

Wang, Linghua, Xi, Liu, Wheeler, David, Hughes, Daniel, Covington, Kyle, Jayaseelan, Joy C., Korchina, Viktoriya, Lewis, Lora, Hu, Jianhong, Doddapaneni, HarshaVardhan, Muzny, Donna, Gibbs, Richard, Hoadley, Katherine A., Hollern, Daniel, Vincent, Benjamin G., Chai, Shengjie, Smith, Christof C., Auman, J. Todd, Shi, Yan, Meng, Shaowu, Skelly, Tara, Tan, Donghui, Veluvolu, Umadevi, Mieczkowski, Piotr A., Jones, Corbin D., Wilkerson, Matthew D., Balu, Saianand, Bodenheimer, Tom, Hoyle, Alan P., Jefferys, Stuart R., Mose, Lisle E., Simons, Janae V., Soloway, Matthew G., Roach, Jeffrey, Parker, Joel S., Hayes, D. Neil, Perou, Charles M., Shih, Juliann, Cherniack, Andrew D., Meyerson, Matthew, Saksena, Gordon, Cibulskis, Carrie, Schumacher, Steven E., Beroukhim, Rameen, Gabriel, Stacey B., Bowlby, Reanne, Mungall, Andrew J., Brooks, Denise, Kasaian, Katayoon, Ally, Adrian, Balasundaram, Miruna, Carlsen, Rebecca, Cheung, Dorothy, Chuah, Eric, Dhalla, Noreen, Holt, Robert A., Jones, Steven J.M., Ma, Yussanne, Mayo, Michael, Moore, Richard A., Robertson, A. Gordon, Schein, Jacqueline E., Sipahimalani, Payal, Tam, Angela, Thiessen, Nina, Wong, Tina, Marra, Marco A., Shen, Hui, Zhou, Wanding, Laird, Peter W., Weisenberger, Daniel J., Van Den Berg, David J., Lai, Phillip H., Berrios, Mario, Holbrook, Andrea, Bootwalla, Moiz S., Maglinte, Dennis T., Armenia, Joshua, Sánchez-Vega, Francisco, Schultz, Nikolaus, Chakravarty, Debyani, Gao, Jianjiong, Heins, Zachary, Kundra, Ritika, Ochoa, Angelica, Liu, Minwei, Sander, Chris, Ladanyi, Marc, Thorsson, Vesteinn, Radenbaugh, Amie J., Newton, Yulia, Stuart, Joshua M., Cho, Juok, Heiman, David I., Noble, Michael S., Zhang, Hailei, Getz, Gad, Gehlenborg, Nils, Voet, Doug, Lin, Pei, Frazer, Scott, Kim, Jaegil, Lawrence, Michael S., Meier, Sam, Defreitas, Timothy, Chin, Lynda, Hegde, Apurva M., Akbani, Rehan, Weinstein, John N., Liu, Wenbin, Mills, Gordon B., Lu, Yiling, Pyle, Louise C., Pluta, John, Nathanson, Katherine L., Tickoo, Satish K., Reuter, Victor E., Mehra, Rohit, Looijenga, Leendert, Bryce, Alan H., Cárcano, Flavio M., Carvalho, André L., Cortessis, Victoria K., Feldman, Darren, Godoy, Guilherme, Ittmann, Michael, Jones, Jeffrey, Kulis, Tomislav, Lerner, Seth, Lessel, Davor, Shelley, Carl S., Vidal, Daniel O., Leraas, Kristen M., Lichtenberg, Tara M., Bowen, Jay, Gastier-Foster, Julie M., Gerken, Mark, Helsel, Carmen, Ramirez, Nilsa C., Wise, Lisa, Zmuda, Erik, Cottingham, Sandra, Chesla, David, Saller, Charles, Tarvin, Katherine, Lopes, Luiz Fernando, Scapulatempo-Neto, Cristovam, Aredes, Natália D.A., Oosterhuis, Wolter, Gillis, Ad, Stoop, Hans, Eijkenboom, Wil, Sandusky, George, Martin, Sue Ellen, Aron, Manju, Daneshmand, Siamak, Djaladat, Hooman, Quinn, David, Dorff, Tanya, Lennerz, Jochen K., Thorne, Leigh B., Gamulin, Marija, Kastelan, Zeljko, Hudolin, Tvrtko, Kubisch, Christian, Boice, Lori, Huang, Mei, Perou, Amy H., Rathmell, W. Kimryn, Pihl, Todd, Wan, Yunhu, Sun, Qiang, Naresh, Rashi, Chudamani, Sudha, Liu, Jia, Lolla, Laxmi, Wu, Ye, Ferguson, Martin L., Zenklusen, Jean C., Felau, Ina, Zhang, Jiashan (Julia), Sheth, Margi, Demchok, John A., Yang, Liming, Wang, Zhining, Tarnuzzer, Roy, Hutter, Carolyn M., Sofia, Heidi J., Davidsen, Tanja M., Hollern, Daniel P., Thorsson, Vésteinn, Feldman, Darren R., ZenKlusen, Jean C., Zhang, Jiashan, and Wheeler, David A.

Published
2018
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31. SHP2 inhibition reduces leukemogenesis in models of combined genetic and epigenetic mutations

Author

Pandey, Ruchi, Ramdas, Baskar, Wan, Changlin, Sandusky, George, Mohseni, Morvarid, Zhang, Chi, and Kapur, Reuben

Subjects
Analysis, Models, Genetic aspects, Prognosis, Chromosomes -- Analysis -- Genetic aspects -- Models, Epigenetic inheritance -- Analysis -- Genetic aspects -- Models, Methylation -- Analysis -- Models, Methyltransferases -- Analysis -- Models, Tyrosine -- Analysis -- Genetic aspects -- Models, Phosphatases -- Analysis -- Genetic aspects -- Models, Gene expression -- Analysis -- Genetic aspects -- Models, Cytokines, Acute myelocytic leukemia, Gilteritinib, Phenols (Class of compounds), Myeloid leukemia, DNA, Genes
Abstract

Introduction Although acute myeloid leukemia (AML) is the second most common form of leukemia, the 5-year survival rate has remained dismally low (~27%). The prognosis is worse for older patients [...], In patients with acute myeloid leukemia (AML), 10% to 30% with the normal karyotype express mutations in regulators of DNA methylation, such as TET2 or DNMT3A, in conjunction with activating mutation in the receptor tyrosine kinase FLT3. These patients have a poor prognosis because they do not respond well to established therapies. Here, utilizing mouse models of AML that recapitulate cardinal features of the human disease and bear a combination of loss-of-function mutations in either Tet2 or Dnmt3a along with expression of [FlT3.sup.ITD], we show that inhibition of the protein tyrosine phosphatase SHP2, which is essential for cytokine receptor signaling (including FLT3), by the small molecule allosteric inhibitor SHP099 impairs growth and induces differentiation of leukemic cells without impacting normal hematopoietic cells. We also show that SHP099 normalizes the gene expression program associated with increased cell proliferation and self-renewal in leukemic cells by downregulating the Myc signature. Our results provide a new and more effective target for treating a subset of patients with AML who bear a combination of genetic and epigenetic mutations.

Published
2019
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34. Table S2 from Combined CDK4/6 and ERK1/2 Inhibition Enhances Antitumor Activity in NF1-Associated Plexiform Neurofibroma

Author

Flint, Alyssa C., primary, Mitchell, Dana K., primary, Angus, Steven P., primary, Smith, Abbi E., primary, Bessler, Waylan, primary, Jiang, Li, primary, Mang, Henry, primary, Li, Xiaohong, primary, Lu, Qingbo, primary, Rodriguez, Brooke, primary, Sandusky, George E., primary, Masters, Andi R., primary, Zhang, Chi, primary, Dang, Pengtao, primary, Koenig, Jenna, primary, Johnson, Gary L., primary, Shen, Weihua, primary, Liu, Jiangang, primary, Aggarwal, Amit, primary, Donoho, Gregory P., primary, Willard, Melinda D., primary, Bhagwat, Shripad V., primary, Clapp, D. Wade, primary, and Rhodes, Steven D., primary

Published
2023
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35. Figure S1 from Combined CDK4/6 and ERK1/2 Inhibition Enhances Antitumor Activity in NF1-Associated Plexiform Neurofibroma

Author

Flint, Alyssa C., primary, Mitchell, Dana K., primary, Angus, Steven P., primary, Smith, Abbi E., primary, Bessler, Waylan, primary, Jiang, Li, primary, Mang, Henry, primary, Li, Xiaohong, primary, Lu, Qingbo, primary, Rodriguez, Brooke, primary, Sandusky, George E., primary, Masters, Andi R., primary, Zhang, Chi, primary, Dang, Pengtao, primary, Koenig, Jenna, primary, Johnson, Gary L., primary, Shen, Weihua, primary, Liu, Jiangang, primary, Aggarwal, Amit, primary, Donoho, Gregory P., primary, Willard, Melinda D., primary, Bhagwat, Shripad V., primary, Clapp, D. Wade, primary, and Rhodes, Steven D., primary

Published
2023
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36. Data from Combined CDK4/6 and ERK1/2 Inhibition Enhances Antitumor Activity in NF1-Associated Plexiform Neurofibroma

Author

Flint, Alyssa C., primary, Mitchell, Dana K., primary, Angus, Steven P., primary, Smith, Abbi E., primary, Bessler, Waylan, primary, Jiang, Li, primary, Mang, Henry, primary, Li, Xiaohong, primary, Lu, Qingbo, primary, Rodriguez, Brooke, primary, Sandusky, George E., primary, Masters, Andi R., primary, Zhang, Chi, primary, Dang, Pengtao, primary, Koenig, Jenna, primary, Johnson, Gary L., primary, Shen, Weihua, primary, Liu, Jiangang, primary, Aggarwal, Amit, primary, Donoho, Gregory P., primary, Willard, Melinda D., primary, Bhagwat, Shripad V., primary, Clapp, D. Wade, primary, and Rhodes, Steven D., primary

Published
2023
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38. Comprehensive Molecular Characterization of Muscle-Invasive Bladder Cancer

Author

Akbani, Rehan, Al-Ahmadie, Hikmat, Albert, Monique, Alexopoulou, Iakovina, Ally, Adrian, Antic, Tatjana, Aron, Manju, Balasundaram, Miruna, Bartlett, John, Baylin, Stephen B., Beaver, Allison, Bellmunt, Joaquim, Birol, Inanc, Boice, Lori, Bootwalla, Moiz S., Bowen, Jay, Bowlby, Reanne, Brooks, Denise, Broom, Bradley M., Bshara, Wiam, Bullman, Susan, Burks, Eric, Cárcano, Flavio M., Carlsen, Rebecca, Carvalho, Benilton S., Carvalho, Andre L., Castle, Eric P., Castro, Mauro A.A., Castro, Patricia, Catto, James W., Chagas, Vinicius S., Cherniack, Andrew D., Chesla, David W., Choo, Caleb, Chuah, Eric, Chudamani, Sudha, Cortessis, Victoria K., Cottingham, Sandra L., Crain, Daniel, Curley, Erin, Czerniak, Bogdan A., Daneshmand, Siamak, Demchok, John A., Dhalla, Noreen, Djaladat, Hooman, Eckman, John, Egea, Sophie C., Engel, Jay, Felau, Ina, Ferguson, Martin L., Gardner, Johanna, Gastier-Foster, Julie M., Gerken, Mark, Getz, Gad, Gibb, Ewan A., Gomez-Fernandez, Carmen R., Gordenin, Dmitry A., Guo, Guangwu, Hansel, Donna E., Harr, Jodi, Hartmann, Arndt, Herbert, Lynn M., Hinoue, Toshinori, Ho, Thai H., Hoadley, Katherine A., Holt, Robert A., Hutter, Carolyn M., Jones, Steven J.M., Jorda, Merce, Kahnoski, Richard J., Kanchi, Rupa S., Kasaian, Katayoon, Kim, Jaegil, Klimczak, Leszek J., Kwiatkowski, David J., Lai, Phillip H., Laird, Peter W., Lane, Brian R., Leraas, Kristen M., Lerner, Seth P., Lichtenberg, Tara M., Liu, Jia, Lolla, Laxmi, Lotan, Yair, Lu, Yiling, Lucchesi, Fabiano R., Ma, Yussanne, Machado, Roberto D., Maglinte, Dennis T., Mallery, David, Marra, Marco A., Martin, Sue E., Mayo, Michael, McConkey, David J., Meraney, Anoop, Meyerson, Matthew, Mills, Gordon B., Moinzadeh, Alireza, Moore, Richard A., Mora Pinero, Edna M., Morris, Scott, Morrison, Carl, Mungall, Karen L., Mungall, Andrew J., Myers, Jerome B., Naresh, Rashi, O'Donnell, Peter H., Ojesina, Akinyemi I., Parekh, Dipen J., Parfitt, Jeremy, Paulauskis, Joseph D., Sekhar Pedamallu, Chandra, Penny, Robert J., Pihl, Todd, Porten, Sima, Quintero-Aguilo, Mario E., Ramirez, Nilsa C., Rathmell, W. Kimryn, Reuter, Victor E., Rieger-Christ, Kimberly, Robertson, A. Gordon, Sadeghi, Sara, Saller, Charles, Salner, Andrew, Sanchez-Vega, Francisco, Sandusky, George, Scapulatempo-Neto, Cristovam, Schein, Jacqueline E., Schuckman, Anne K., Schultz, Nikolaus, Shelton, Candace, Shelton, Troy, Shukla, Sachet A., Simko, Jeff, Singh, Parminder, Sipahimalani, Payal, Smith, Norm D., Sofia, Heidi J., Sorcini, Andrea, Stanton, Melissa L., Steinberg, Gary D., Stoehr, Robert, Su, Xiaoping, Sullivan, Travis, Sun, Qiang, Tam, Angela, Tarnuzzer, Roy, Tarvin, Katherine, Taubert, Helge, Thiessen, Nina, Thorne, Leigh, Tse, Kane, Tucker, Kelinda, Van Den Berg, David J., van Kessel, Kim E., Wach, Sven, Wan, Yunhu, Wang, Zhining, Weinstein, John N., Weisenberger, Daniel J., Wise, Lisa, Wong, Tina, Wu, Ye, Wu, Catherine J., Yang, Liming, Zach, Leigh Anne, Zenklusen, Jean C., Zhang, Jiashan (Julia), Zhang, Jiexin, Zmuda, Erik, Zwarthoff, Ellen C., de Sa Carvalho, Benilton, Pedamallu, Chandra Sekhar, and Schultz, Nicholaus

Published
2017
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40. Publisher Correction: Regulation of cellular sterol homeostasis by the oxygen responsive noncoding RNA lincNORS

Author

Wu, Xue, Niculite, Cristina M., Preda, Mihai Bogdan, Rossi, Annalisa, Tebaldi, Toma, Butoi, Elena, White, Mattie K., Tudoran, Oana M., Petrusca, Daniela N., Jannasch, Amber S., Bone, William P., Zong, Xingyue, Fang, Fang, Burlacu, Alexandrina, Paulsen, Michelle T., Hancock, Brad A., Sandusky, George E., Mitra, Sumegha, Fishel, Melissa L., Buechlein, Aaron, Ivan, Cristina, Oikonomopoulos, Spyros, Gorospe, Myriam, Mosley, Amber, Radovich, Milan, Davé, Utpal P., Ragoussis, Jiannis, Nephew, Kenneth P., Mari, Bernard, McIntyre, Alan, Konig, Heiko, Ljungman, Mats, Cousminer, Diana L., Macchi, Paolo, and Ivan, Mircea

Published
2020
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41. Regulation of cellular sterol homeostasis by the oxygen responsive noncoding RNA lincNORS

Author

Wu, Xue, Niculite, Cristina M., Preda, Mihai Bogdan, Rossi, Annalisa, Tebaldi, Toma, Butoi, Elena, White, Mattie K., Tudoran, Oana M., Petrusca, Daniela N., Jannasch, Amber S., Bone, William P., Zong, Xingyue, Fang, Fang, Burlacu, Alexandrina, Paulsen, Michelle T., Hancock, Brad A., Sandusky, George E., Mitra, Sumegha, Fishel, Melissa L., Buechlein, Aaron, Ivan, Cristina, Oikonomopoulos, Spyros, Gorospe, Myriam, Mosley, Amber, Radovich, Milan, Davé, Utpal P., Ragoussis, Jiannis, Nephew, Kenneth P., Mari, Bernard, McIntyre, Alan, Konig, Heiko, Ljungman, Mats, Cousminer, Diana L., Macchi, Paolo, and Ivan, Mircea

Published
2020
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42. Comprehensive Molecular Characterization of Pheochromocytoma and Paraganglioma

Author

Akbani, Rehan, Ally, Adrian, Amar, Laurence, Amelio, Antonio L., Arachchi, Harindra, Asa, Sylvia L., Auchus, Richard J., Auman, J. Todd, Baertsch, Robert, Balasundaram, Miruna, Balu, Saianand, Bartsch, Detlef K., Baudin, Eric, Bauer, Thomas, Beaver, Allison, Benz, Christopher, Beroukhim, Rameen, Beuschlein, Felix, Bodenheimer, Tom, Boice, Lori, Bowen, Jay, Bowlby, Reanne, Brooks, Denise, Carlsen, Rebecca, Carter, Suzie, Cassol, Clarissa A., Cherniack, Andrew D., Chin, Lynda, Cho, Juok, Chuah, Eric, Chudamani, Sudha, Cope, Leslie, Crain, Daniel, Curley, Erin, Danilova, Ludmila, de Cubas, Aguirre A., de Krijger, Ronald R., Demchok, John A., Deutschbein, Timo, Dhalla, Noreen, Dimmock, David, Dinjens, Winand N.M., Else, Tobias, Eng, Charis, Eschbacher, Jennifer, Fassnacht, Martin, Felau, Ina, Feldman, Michael, Ferguson, Martin L., Fiddes, Ian, Fishbein, Lauren, Frazer, Scott, Gabriel, Stacey B., Gardner, Johanna, Gastier-Foster, Julie M., Gehlenborg, Nils, Gerken, Mark, Getz, Gad, Geurts, Jennifer, Ghayee, Hans K., Gimenez-Roqueplo, Anne-Paule, Giordano, Thomas J., Goldman, Mary, Graim, Kiley, Gupta, Manaswi, Haan, David, Hahner, Stefanie, Hantel, Constanze, Haussler, David, Hayes, D. Neil, Heiman, David I., Hoadley, Katherine A., Holt, Robert A., Hoyle, Alan P., Huang, Mei, Hunt, Bryan, Hutter, Carolyn M., Jefferys, Stuart R., Johnson, Amy R., Jones, Steven J.M., Jones, Corbin D., Kasaian, Katayoon, Kebebew, Electron, Kim, Jaegil, Kimes, Patrick, Knijnenburg, Theo, Korpershoek, Esther, Lander, Eric, Lawrence, Michael S., Lechan, Ronald, Lee, Darlene, Leraas, Kristen M., Lerario, Antonio, Leshchiner, Ignaty, Lichtenberg, Tara M., Lin, Pei, Ling, Shiyun, Liu, Jia, LiVolsi, Virginia A., Lolla, Laxmi, Lotan, Yair, Lu, Yiling, Ma, Yussanne, Maison, Nicole, Makowski, Liza, Mallery, David, Mannelli, Massimo, Marquard, Jessica, Marra, Marco A., Matthew, Thomas, Mayo, Michael, Méatchi, Tchao, Meng, Shaowu, Merino, Maria J., Mete, Ozgur, Meyerson, Matthew, Mieczkowski, Piotr A., Mills, Gordon B., Moore, Richard A., Morozova, Olena, Morris, Scott, Mose, Lisle E., Mungall, Andrew J., Murray, Bradley A., Naresh, Rashi, Nathanson, Katherine L., Newton, Yulia, Ng, Sam, Ni, Ying, Noble, Michael S., Nwariaku, Fiemu, Pacak, Karel, Parker, Joel S., Paul, Evan, Penny, Robert, Perou, Charles M., Perou, Amy H., Pihl, Todd, Powers, James, Rabaglia, Jennifer, Radenbaugh, Amie, Ramirez, Nilsa C., Rao, Arjun, Rathmell, W. Kimryn, Riester, Anna, Roach, Jeffrey, Robertson, A. Gordon, Sadeghi, Sara, Saksena, Gordon, Salama, Sofie, Saller, Charles, Sandusky, George, Sbiera, Silviu, Schein, Jacqueline E., Schumacher, Steven E., Shelton, Candace, Shelton, Troy, Sheth, Margi, Shi, Yan, Shih, Juliann, Shmulevich, Ilya, Simons, Janae V., Sipahimalani, Payal, Skelly, Tara, Sofia, Heidi J., Sokolov, Artem, Soloway, Matthew G., Sougnez, Carrie, Stuart, Josh, Sun, Charlie, Swatloski, Teresa, Tam, Angela, Tan, Donghui, Tarnuzzer, Roy, Tarvin, Katherine, Thiessen, Nina, Thorne, Leigh B., Timmers, Henri J., Tischler, Arthur S., Tse, Kane, Uzunangelov, Vlado, van Berkel, Anouk, Veluvolu, Umadevi, Vicha, Ales, Voet, Doug, Waldmann, Jens, Walter, Vonn, Wan, Yunhu, Wang, Zhining, Wang, Tracy S., Weaver, Joellen, Weinstein, John N., Weismann, Dirk, Wenz, Brandon, Wilkerson, Matthew D., Wise, Lisa, Wong, Tina, Wong, Christopher, Wu, Ye, Yang, Liming, Zelinka, Tomas, Zenklusen, Jean C., Zhang, Jiashan (Julia), Zhang, Wei, Zhu, Jingchun, Zinzindohoué, Franck, and Zmuda, Erik

Published
2017
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43. BRCA1 and BRCA2 germline mutations driven signaling pathway alterations are sufficient to initiate breast tumorigenesis by the PIK3CAH1047Roncogene

Author

Bhat-Nakshatri, Poornima, primary, Khatpe, Aditi, additional, Chen, Duojiao, additional, Batic, Katie, additional, Mang, Henry, additional, Herodotou, Christopher, additional, McGuire, Patrick C., additional, Xuei, Xiaoling, additional, Gao, Hongyu, additional, Liu, Yunlong, additional, Sandusky, George, additional, Storniolo, Anna Maria, additional, and Nakshatri, Harikrishna, additional

Published
2023
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44. Combined CDK4/6 and ERK1/2 Inhibition Enhances Antitumor Activity in NF1-Associated Plexiform Neurofibroma

Author

Flint, Alyssa C., primary, Mitchell, Dana K., additional, Angus, Steven P., additional, Smith, Abbi E., additional, Bessler, Waylan, additional, Jiang, Li, additional, Mang, Henry, additional, Li, Xiaohong, additional, Lu, Qingbo, additional, Rodriguez, Brooke, additional, Sandusky, George E., additional, Masters, Andi R., additional, Zhang, Chi, additional, Dang, Pengtao, additional, Koenig, Jenna, additional, Johnson, Gary L., additional, Shen, Weihua, additional, Liu, Jiangang, additional, Aggarwal, Amit, additional, Donoho, Gregory P., additional, Willard, Melinda D., additional, Bhagwat, Shripad V., additional, Clapp, D. Wade, additional, and Rhodes, Steven D., additional

Published
2023
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45. Atractylenolide I enhances responsiveness to immune checkpoint blockade therapy by activating tumor antigen presentation

Author

Xu, Hanchen, Van der Jeught, Kevin, Zhou, Zhuolong, Zhang, Lu, Yu, Tao, Sun, Yifan, Li, Yujing, Wan, Changlin, So, Ka Man, Liu, Degang, Frieden, Michael, Fang, Yuanzhang, Mosley, Amber L., He, Xiaoming, Zhang, Xinna, Sandusky, George E., Liu, Yunlong, Meroueh, Samy O., Zhang, Chi, Wijeratne, Aruna B., Huang, Cheng, Ji, Guang, and Lu, Xiongbin

Subjects
Colorectal cancer -- Care and treatment, Immunotherapy -- Management, Cancer -- Care and treatment, Cell-mediated cytotoxicity -- Health aspects, Phytochemicals -- Usage -- Physiological aspects -- Health aspects, Tumor antigens -- Physiological aspects -- Health aspects, Atractylodes -- Chemical properties -- Health aspects, Company business management, Health care industry
Abstract

One of the primary mechanisms of tumor cell immune evasion is the loss of antigenicity, which arises due to lack of immunogenic tumor antigens as well as dysregulation of the antigen processing machinery. In a screen for small-molecule compounds from herbal medicine that potentiate T cell-mediated cytotoxicity, we identified atractylenolide I (ATT-I), which substantially promotes tumor antigen presentation of both human and mouse colorectal cancer (CRC) cells and thereby enhances the cytotoxic response of [CD8.sup.+] T cells. Cellular thermal shift assay (CETSA) with multiplexed quantitative mass spectrometry identified the proteasome 26S subunit non-ATPase 4 (PSMD4), an essential component of the immunoproteasome complex, as a primary target protein of ATT-I. Binding of ATT-I with PSMD4 augments the antigen-processing activity of immunoproteasome, leading to enhanced MHC-I-mediated antigen presentation on cancer cells. In syngeneic mouse CRC models and human patient-derived CRC organoid models, ATT-I treatment promotes the cytotoxicity of [CD8.sup.+] T cells and thus profoundly enhances the efficacy of immune checkpoint blockade therapy. Collectively, we show here that targeting the function of immunoproteasome with ATT-I promotes tumor antigen presentation and empowers T cell cytotoxicity, thus elevating the tumor response to immunotherapy., Introduction Current cancer immunotherapy is based on the longstanding immune surveillance hypotheses originating from the beginning of the 20th century. Regardless of diverse forms of cancer immunotherapy, they all share [...]

Published
2021
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49. Loss of Dnmt3a impairs hematopoietic homeostasis and myeloid cell skewing via the PI3Kinase pathway

Author

Palam, Lakshmi Reddy, primary, Ramdas, Baskar, additional, Pickerell, Katelyn, additional, Pasupuleti, Santhosh Kumar, additional, Kanumuri, Rahul, additional, Cesarano, Annamaria, additional, Szymanski, Megan, additional, Selman, Bryce, additional, Dave, Utpal P., additional, Sandusky, George, additional, Perna, Fabiana, additional, Paczesny, Sophie, additional, and Kapur, Reuben, additional

Published
2023
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50. Data from TONSL Is an Immortalizing Oncogene and a Therapeutic Target in Breast Cancer

Author

Khatpe, Aditi S., primary, Dirks, Rebecca, primary, Bhat-Nakshatri, Poornima, primary, Mang, Henry, primary, Batic, Katie, primary, Swiezy, Sarah, primary, Olson, Jacob, primary, Rao, Xi, primary, Wang, Yue, primary, Tanaka, Hiromi, primary, Liu, Sheng, primary, Wan, Jun, primary, Chen, Duojiao, primary, Liu, Yunlong, primary, Fang, Fang, primary, Althouse, Sandra, primary, Hulsey, Emily, primary, Granatir, Maggie M., primary, Addison, Rebekah, primary, Temm, Constance J., primary, Sandusky, George, primary, Lee-Gosselin, Audrey, primary, Nephew, Kenneth, primary, Miller, Kathy D., primary, and Nakshatri, Harikrishna, primary

Published
2023
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