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48 results on '"Lacorazza, H. Daniel"'

7. An ELF4 hypomorphic variant results in NK cell deficiency

Author

Salinas, Sandra Andrea, primary, Mace, Emily M., additional, Conte, Matilde I., additional, Park, Chun Shik, additional, Li, Yu, additional, Rosario-Sepulveda, Joshua I., additional, Mahapatra, Sanjana, additional, Moore, Emily K., additional, Hernandez, Evelyn R., additional, Chinn, Ivan K., additional, Reed, Abigail E., additional, Lee, Barclay J., additional, Frumovitz, Alexander, additional, Gibbs, Richard A., additional, Posey, Jennifer E., additional, Forbes Satter, Lisa R., additional, Thatayatikom, Akaluck, additional, Allenspach, Eric J., additional, Wensel, Theodore G., additional, Lupski, James R., additional, Lacorazza, H. Daniel, additional, and Orange, Jordan S., additional

Published
2022
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8. Relocalization of PU.1 Underlies the On- and Off-Tumor Effects of SWI/SNF Blockade in AML

Author

Chambers, Courtney, primary, Kurtz, Kristen, additional, Lewis, Andrew Henry, additional, Wohlan, Katharina, additional, Chan, Yuen San, additional, Cermakova, Katerina, additional, Dejmek, Milan, additional, Sala, Michal, additional, Aguilar, Rogelio, additional, Loeza Cabrera, Mario, additional, Nencka, Radim, additional, Lacorazza, H. Daniel, additional, Rau, Rachel E., additional, and Hodges, H. Courtney, additional

Published
2022
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19. The Transcription Factor ELF4 Suppresses Differentiation of Proliferating CD4+ T Cells to the Th17 Lineage

Author

Lee, Ping-Hsien, Puppi, Monica, Schluns, Kimberly S., Yu-Lee, Li-Yuan, Dong, Chen, and Lacorazza, H. Daniel

Subjects
CD4-Positive T-Lymphocytes, Mice, Knockout, Cell Survival, Cell Differentiation, Lymphocyte Activation, Article, Cell Line, DNA-Binding Proteins, Mice, Animals, Cytokines, Humans, Th17 Cells, Transcription Factors
Abstract

The differentiation of CD4(+) T cells into different Th lineages is driven by cytokine milieu in the priming site and the underlying transcriptional circuitry. Even though many positive regulators have been identified, it is not clear how this process is inhibited at transcriptional level. In this study, we report that the E-twenty six (ETS) transcription factor E74-like factor 4 (ELF4) suppresses the differentiation of Th17 cells both in vitro and in vivo. Culture of naive Elf4(-/-) CD4(+) T cells in the presence of IL-6 and TGF-β (or IL-6, IL-23, and IL-1β) resulted in increased numbers of IL-17A-positive cells compared with wild-type controls. In contrast, the differentiation to Th1, Th2, or regulatory T cells was largely unaffected by loss of ELF4. The increased expression of genes involved in Th17 differentiation observed in Elf4(-/-) CD4(+) T cells suggested that ELF4 controls their programming into the Th17 lineage rather than only IL-17A gene expression. Despite normal proliferation of naive CD4(+) T cells, loss of ELF4 lowered the requirement of IL-6 and TGF-β signaling for IL-17A induction in each cell division. ELF4 did not inhibit Th17 differentiation by promoting IL-2 production as proposed for another ETS transcription factor, ETS1. Elf4(-/-) mice showed increased numbers of Th17 cells in the lamina propria at steady state, in lymph nodes after immunization, and, most importantly, in the CNS following experimental autoimmune encephalomyelitis induction, contributing to the increased disease severity. Collectively, our findings suggest that ELF4 restrains Th17 differentiation in dividing CD4(+) T cells by regulating commitment to the Th17 differentiation program.

Published
2013

21. The transcription factor ELF4 controls quiescence of endothelial cells and their resistance to myeloablative treatments in bone marrow

Author

Sivina, Mariela, Yamada, Takeshi, Park, Chun Shik, Puppi, Monica, Coskun, Suleyman, Hirschi, Karen, and Lacorazza, H. Daniel

Subjects
Mice, Knockout, Time Factors, Cell Cycle, Drug Resistance, Cyclin-Dependent Kinase 4, Endothelial Cells, Neovascularization, Physiologic, Bone Marrow Cells, Myeloablative Agonists, Transfection, Article, DNA-Binding Proteins, Mice, Inbred C57BL, Mice, COS Cells, Chlorocebus aethiops, NIH 3T3 Cells, Animals, Humans, RNA Interference, Fluorouracil, Promoter Regions, Genetic, Cellular Senescence, Cell Proliferation, Transcription Factors
Abstract

The regeneration of the hematopoietic system in bone marrow after chemotherapy depends on a balance between the quiescence and proliferation of lineage-specific progenitor cells. Even though the vascular network in bone is damaged by cytoablation, the transcriptional control of quiescence in endothelial cells is not well known. In this study, we investigated the role of the transcription factor E74-like factor (ELF4) in the proliferation of endothelial cells in bone marrow.Loss-of-function models were used to study the role of ELF4 in human and murine endothelial cells. ELF4 promotes cell cycle entry by activating cyclin-dependent kinase-4 in human umbilical vein endothelial cells. Elf4-null mice exhibited enhanced recovery of bone marrow CD45- CD31+ endothelial cells and sinusoidal blood vessels following administration of 5-fluorouracil.Loss of ELF4 leads to increased quiescence in bone marrow endothelial cells by the deregulation of cyclin-dependent kinase-4 expression and to enhanced regeneration of sinusoidal blood vessels.

Published
2011

42. The ETS Protein MEF Plays a Critical Role in Perforin Gene Expression and the Development of Natural Killer and NK-T Cells

Author

Lacorazza, H. Daniel, Miyazaki, Yasushi, Di Cristofano, Antonio, Deblasio, Anthony, Hedvat, Cyrus, Zhang, Jin, Cordon-Cardo, Carlos, Mao, Shifeng, Pandolfi, Pier Paolo, and Nimer, Stephen D.

Subjects
*GENE expression, *KILLER cells, *T cells
Abstract

We utilized gene targeting by homologous recombination to define the role that MEF, a transcriptional activating member of the ETS family of transcription factors, plays in lymphopoiesis. MEF−/− mice have a profound reduction in the number of NK-T and NK cells. Purified MEF−/− NK cells cannot lyse tumor cell targets and secrete only minimal amounts of IFNγ. Perforin protein expression is severely impaired in MEF-deficient NK cells, likely accounting for the lack of tumor cell cytotoxicity. Promoter studies and chromatin immunoprecipitation analyses demonstrate that MEF and not ETS-1 directly regulates transcription of the perforin gene in NK cells. Our results uncover a specific role of MEF in the development and function of NK cells and in innate immunity. [Copyright &y& Elsevier]

Published
2002
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43. Retrovirus-Mediated Gene Transfer and Expression of Human Ornithine -Aminotransferase into Embryonic Fibroblasts

Author

Rivero, J. Luis, Lacorazza, H. Daniel, Kozhich, Alexander, Nussenblatt, Robert B., and Jendoubi, Moncef

Abstract

ABSTRACTOrnithine aminotransferase (OAT) is a nuclear-encoded mitochondrial matrix enzyme that catalyzes the reversible transamination of ornithine to glutamate semialdehyde. In humans, genetic deficiency of OAT results in gyrate atrophy of the choroid and retina, a blinding chorioretinal degeneration usually beginning in late childhood. This disorder has been shown to be autosomal recessive, and is often caused by missense, nonsense, and/or frameshift mutations in the OAT gene.With the view of applying gene therapy, a Moloney murine leukemia virus (MoMLV)-based recombinant retrovirus vector has been constructed. The human OAT cDNA was placed under the control of the enhancerpromoter regulatory elements derived from the MoMLV long terminal repeat (LTR). The construct was transfected into the retroviral packaging cell lines GP E 86 and CRIP to produce virus particles. Supernatant from these OAT retrovirus producer cell lines were used to transduce mouse C57B1/6 embryonal fibroblasts. We showed that the recombinant retrovirus transfers the OAT gene to the recipient cells, which produce an OAT RNA transcript when analyzed by Northern blot. Western blot analysis and enzymatic assays confirmed the presence of an OAT polypeptide that has a high enzymatic activity in the transduced cell lines, even after a long period of time in vitro.

Published
1994
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44. A Novel Short Latency, High Penetrance Model of KRASMutation-Driven T-Cell Acute Lymphoblastic Leukemia

Author

Junco, Jacob J., Gant, Vincent Ulysses, Terrell, Maci S., Miller, Matthew Benjamin, Park, Chun Shik, Chen, Taylor J, Lacorazza, H. Daniel, Goodell, Margaret, Rau, Rachel E., and Rabin, Karen R.

Abstract

Introduction: RAS-activating mutations are common in both childhood B- and T-acute lymphoblastic leukemia (ALL). Prior studies of B- and T-ALL have shown that RASmutations become enriched during treatment in minimum residual disease-positive cases, are associated with a poor glucocorticoid response, and are associated with inferior survival in relapsed disease. There is a need for more tractable preclinical models of RASmutation-driven B- and T-ALL. Currently, most genetically-engineered mouse models generated to study KRASG12D-driven ALL have a high latency, low penetrance, and/or necessitate the use of multiple technical manipulations, which can yield inconsistent results. Here, we set out to generate a more efficient and penetrant mouse model of KRASG12D-driven B-ALL or T-ALL.

Published
2019
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45. Vitamin K3 (menadione) Induces Cytotoxicity in Chronic Myeloid Leukemia Stem Cells By Upregulating DYRK2 through the Inhibition of SIAH2 Ubiquitin Ligase

Author

Park, Chun Shik, Shen, Ye, Lewis, Andrew H, Suppipat, Koramit, Puppi, Monica, Tomolonis, Julie, Chen, Taylor J, Pang, Paul, Mistretta, Toni-Ann, Ma, Leyuan, Green, Michael R, Rau, Rachel E., and Lacorazza, H. Daniel

Abstract

Leukemic stem cells (LSCs) generated by the transformation of normal hematopoietic stem cells (HSCs) by BCR-ABL are elusive targets that can initiate and sustain leukemia owing to their unique capacity to regenerate themselves during cell division (self-renewal) and differentiate into a bulk of leukemia cells. Although chronic myeloid leukemia (CML) can be successfully managed using tyrosine kinase inhibitors (TKIs), drug discontinuation trials have shown that 30-60% of patients, depending on the drug used for first- and second-line treatment, can remain in treatment-free remission. Thus, discontinuation is still considered experimental and there are not safety guidelines to stop treatment. A better understanding of self-renewal mechanisms in LSCs will support the development of LSC-specific drugs to induce treatment-free remission in chronic-phase patients by eradicating BCR-ABL-positive LSCs. We recently discovered in mouse models that deletion of the Klf4gene encoding for the transcription factor KLF4 severely abrogated progression of BCR-ABL(p210)-induced CML by impairing survival and self-renewal of LSCs but not normal hematopoietic stem cells (HSCs). Mechanistically, KLF4 represses the Dyrk2gene and thus loss-of-KLF4 resulted in elevated DYRK2 protein levels, which was associated with p53-mediated apoptosis and inhibition of self-renewal via depletion of c-Myc protein in LSCs and not in normal HSCs. Here, we report that this mechanism is active in bone marrow cells from chronic-phase CML patients and that stabilization of DYRK2 protein by inhibition of the ubiquitin E3 ligase with vitamin K3 (VK3) has the potential therapeutic approach. Treatment of CML cell lines and bone marrow cells from CML patients with VK3 induced dose-dependent cytotoxicity and apoptosis. This was correlated with increased DYRK2 expression, depletion of c-Myc, and activation of p53-mediated apoptosis. Most importantly, VK3 induced DYRK2 expression and abrogated capacity of purified CD34+CML stem cells, but not normal CD34+cells, to generate colonies in methylcellulose assays. Cytotoxicity of VK3 largely depended on the expression of DYRK2, the reduced form menadiol inhibited cell viability similarly to menadione (VK3), and the presence of p53 enhanced cytotoxicity by inducing apoptosis in addition to inhibition of self-renewal. VK3 augmented cytotoxicity of Imatinib in CML cell lines and inhibited cell survival in Imatinib-resistant CML cells. The ability to target CML LSCs was confirmed by in vivoadministration of VK3 in BCR-ABL induced mouse model followed by transplantation of leukemic bone marrow in secondary recipient mice. Altogether, our results suggest that stabilization of DYRK2 by inhibition of SIAH2 can induce apoptosis in bulk leukemia cells and LSCs by activating p53 and depleting c-Myc.

Published
2017
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47. SWI/SNF Blockade Disrupts PU.1-Directed Enhancer Programs in Normal Hematopoietic Cells and Acute Myeloid Leukemia.

Author

Chambers C, Cermakova K, Chan YS, Kurtz K, Wohlan K, Lewis AH, Wang C, Pham A, Dejmek M, Sala M, Loeza Cabrera M, Aguilar R, Nencka R, Lacorazza HD, Rau RE, and Hodges HC

Subjects
Animals, Mice, Humans, Bone Marrow pathology, Promoter Regions, Genetic, Cell Differentiation, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute metabolism, Leukopenia genetics
Abstract

In acute myeloid leukemia (AML), SWI/SNF chromatin remodeling complexes sustain leukemic identity by driving high levels of MYC. Previous studies have implicated the hematopoietic transcription factor PU.1 (SPI1) as an important target of SWI/SNF inhibition, but PU.1 is widely regarded to have pioneer-like activity. As a result, many questions have remained regarding the interplay between PU.1 and SWI/SNF in AML as well as normal hematopoiesis. Here we found that PU.1 binds to most of its targets in a SWI/SNF-independent manner and recruits SWI/SNF to promote accessibility for other AML core regulatory factors, including RUNX1, LMO2, and MEIS1. SWI/SNF inhibition in AML cells reduced DNA accessibility and binding of these factors at PU.1 sites and redistributed PU.1 to promoters. Analysis of nontumor hematopoietic cells revealed that similar effects also impair PU.1-dependent B-cell and monocyte populations. Nevertheless, SWI/SNF inhibition induced profound therapeutic response in an immunocompetent AML mouse model as well as in primary human AML samples. In vivo, SWI/SNF inhibition promoted leukemic differentiation and reduced the leukemic stem cell burden in bone marrow but also induced leukopenia. These results reveal a variable therapeutic window for SWI/SNF blockade in AML and highlight important off-tumor effects of such therapies in immunocompetent settings., Significance: Disruption of PU.1-directed enhancer programs upon SWI/SNF inhibition causes differentiation of AML cells and induces leukopenia of PU.1-dependent B cells and monocytes, revealing the on- and off-tumor effects of SWI/SNF blockade., (©2023 The Authors; Published by the American Association for Cancer Research.)

Published
2023
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48. Kruppel-like factor 4 (KLF4) promotes the survival of natural killer cells and maintains the number of conventional dendritic cells in the spleen.

Author

Park CS, Lee PH, Yamada T, Burns A, Shen Y, Puppi M, and Lacorazza HD

Subjects
Animals, Apoptosis, Blotting, Western, Bone Marrow Transplantation, Cell Differentiation, Dendritic Cells immunology, Female, Flow Cytometry, Immunophenotyping, Integrases metabolism, Interferon-gamma metabolism, Killer Cells, Natural immunology, Kruppel-Like Factor 4, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, RNA, Messenger genetics, Real-Time Polymerase Chain Reaction, Spleen immunology, Spleen metabolism, Dendritic Cells cytology, Dendritic Cells metabolism, Killer Cells, Natural cytology, Killer Cells, Natural metabolism, Kruppel-Like Transcription Factors physiology, Spleen cytology
Abstract

The development and survival of NK cells rely on a complex, spatiotemporal gene expression pattern regulated by specific transcription factors in NK cells and tissue-specific microenvironments supported by hematopoietic cells. Here, we show that somatic deletion of the KLF4 gene, using inducible and lineage-specific cre-transgenic mice, leads to a significant reduction of NK cells (NK1.1(+) TCR-β(-)) in the blood and spleen but not in the BM, liver, or LNs. Functional and immunophenotypic analyses revealed increased apoptosis of CD27(+/-) CD11b(+) NK cells in the spleen of KLF4-deficient mice, although remaining NK cells were able to lyse tumor target cells and produce IFN-γ. A normal recovery of adoptively transferred KLF4-deficient NK cells in WT hosts suggested that the survival defect was not intrinsic of NK cells. However, BM chimeras using KLF4-deficient mice as donors indicated that reduced survival of NK cells depended on BM-derived hematopoietic cells in the spleen. The number of CD11c(hi) DCs, which are known to support NK cell survival, was reduced significantly in the spleen of KLF4-deficient mice, likely a result of a lower number of precDC progenitor cells in this tissue. Taken together, our data suggest that the pluripotency-associated gene KLF4 is required for the maintenance of DCs in the spleen and consequently, survival of differentiated NK cells in this tissue.

Published
2012
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