المؤلفون: Kusuma, Frances Karla, Prabhu, Aishvaryaa, Tieo, Galen, Ahmed, Syed Moiz, Dakle, Pushkar, Yong, Wai Khang, Pathak, Elina, Madan, Vikas, Jiang, Yan Yi, Tam, Wai Leong, Kappei, Dennis, Dröge, Peter, Koeffler, H Phillip, Jeitany, Maya

المصدر: Nature Communications. 14(1)

مصطلحات موضوعية: Biological Sciences, Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Orphan Drug, Rare Diseases, Cancer, Genetics, Aetiology, 5.1 Pharmaceuticals, 2.1 Biological and endogenous factors, Development of treatments and therapeutic interventions, Telomere, Cell Survival, Signal Transduction, Gene Expression Regulation, DNA Repair, DNA Replication, JNK Mitogen-Activated Protein Kinases, Humans, Animals, Mice, Cell Line, Tumor

الوصف: Alternative lengthening of telomeres (ALT) supports telomere maintenance in 10-15% of cancers, thus representing a compelling target for therapy. By performing anti-cancer compound library screen on isogenic cell lines and using extrachromosomal telomeric C-circles, as a bona fide marker of ALT activity, we identify a receptor tyrosine kinase inhibitor ponatinib that deregulates ALT mechanisms, induces telomeric dysfunction, reduced ALT-associated telomere synthesis, and targets, in vivo, ALT-positive cells. Using RNA-sequencing and quantitative phosphoproteomic analyses, combined with C-circle level assessment, we find an ABL1-JNK-JUN signalling circuit to be inhibited by ponatinib and to have a role in suppressing telomeric C-circles. Furthermore, transcriptome and interactome analyses suggest a role of JUN in DNA damage repair. These results are corroborated by synergistic drug interactions between ponatinib and either DNA synthesis or repair inhibitors, such as triciribine. Taken together, we describe here a signalling pathway impacting ALT which can be targeted by a clinically approved drug.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/2hd581s8Test

المؤلفون: Togami, Katsuhiro, Chung, Sun Sook, Madan, Vikas, Booth, Christopher AG, Kenyon, Christopher M, Cabal-Hierro, Lucia, Taylor, Justin, Kim, Sunhee S, Griffin, Gabriel K, Ghandi, Mahmoud, Li, Jia, Li, Yvonne Y, Angelot-Delettre, Fanny, Biichle, Sabeha, Seiler, Michael, Buonamici, Silvia, Lovitch, Scott B, Louissaint, Abner, Morgan, Elizabeth A, Jardin, Fabrice, Piccaluga, Pier Paolo, Weinstock, David M, Hammerman, Peter S, Yang, Henry, Konopleva, Marina, Pemmaraju, Naveen, Garnache-Ottou, Francine, Abdel-Wahab, Omar, Koeffler, H Phillip, Lane, Andrew A

المصدر: Cancer Discovery. 12(2)

مصطلحات موضوعية: Rare Diseases, Clinical Research, Cancer, Hematology, Genetics, Aetiology, 2.1 Biological and endogenous factors, Inflammatory and immune system, Apoptosis, Dendritic Cells, Female, Gender Identity, Humans, Male, Mutation, Myeloproliferative Disorders, Ribonucleoproteins, Oncology and Carcinogenesis

الوصف: Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive leukemia of plasmacytoid dendritic cells (pDC). BPDCN occurs at least three times more frequently in men than in women, but the reasons for this sex bias are unknown. Here, studying genomics of primary BPDCN and modeling disease-associated mutations, we link acquired alterations in RNA splicing to abnormal pDC development and inflammatory response through Toll-like receptors. Loss-of-function mutations in ZRSR2, an X chromosome gene encoding a splicing factor, are enriched in BPDCN, and nearly all mutations occur in males. ZRSR2 mutation impairs pDC activation and apoptosis after inflammatory stimuli, associated with intron retention and inability to upregulate the transcription factor IRF7. In vivo, BPDCN-associated mutations promote pDC expansion and signatures of decreased activation. These data support a model in which male-biased mutations in hematopoietic progenitors alter pDC function and confer protection from apoptosis, which may impair immunity and predispose to leukemic transformation. SIGNIFICANCE: Sex bias in cancer is well recognized, but the underlying mechanisms are incompletely defined. We connect X chromosome mutations in ZRSR2 to an extremely male-predominant leukemia. Aberrant RNA splicing induced by ZRSR2 mutation impairs dendritic cell inflammatory signaling, interferon production, and apoptosis, revealing a sex- and lineage-related tumor suppressor pathway.This article is highlighted in the In This Issue feature, p. 275.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/9t7460j7Test

المؤلفون: Jeitany, Maya, Prabhu, Aishvaryaa, Dakle, Pushkar, Pathak, Elina, Madan, Vikas, Kanojia, Deepika, Mukundan, Vineeth, Jiang, Yan Yi, Landesman, Yosef, Tam, Wai Leong, Kappei, Dennis, Koeffler, H Phillip

المصدر: Cellular and Molecular Life Sciences. 78(4)

مصطلحات موضوعية: Biochemistry and Cell Biology, Biomedical and Clinical Sciences, Biological Sciences, Rare Diseases, Biotechnology, Cancer, Hematology, Development of treatments and therapeutic interventions, 5.1 Pharmaceuticals, 2.1 Biological and endogenous factors, Aetiology, Antineoplastic Combined Chemotherapy Protocols, Bortezomib, Cell Line, Tumor, Cell Nucleus, Drug Resistance, Neoplasm, Drug Synergism, Fatty Acid Desaturases, Gene Expression Regulation, Neoplastic, Humans, Hydrazines, Karyopherins, Liposarcoma, Oligopeptides, Piperazines, Proteasome Endopeptidase Complex, Proteasome Inhibitors, Receptors, Cytoplasmic and Nuclear, Triazoles, Proteasome inhibitors, Combinational therapies, Physiology, Clinical Sciences, Biochemistry & Molecular Biology, Biochemistry and cell biology, Medical biochemistry and metabolomics, Oncology and carcinogenesis

الوصف: Proteasome inhibitors, such as bortezomib and carfilzomib, have shown efficacy in anti-cancer therapy in hematological diseases but not in solid cancers. Here, we found that liposarcomas (LPS) are susceptible to proteasome inhibition, and identified drugs that synergize with carfilzomib, such as selinexor, an inhibitor of XPO1-mediated nuclear export. Through quantitative nuclear protein profiling and phospho-kinase arrays, we identified potential mode of actions of this combination, including interference with ribosome biogenesis and inhibition of pro-survival kinase PRAS40. Furthermore, by assessing global protein levels changes, FADS2, a key enzyme regulating fatty acids synthesis, was found down-regulated after proteasome inhibition. Interestingly, SC26196, an inhibitor of FADS2, synergized with carfilzomib. Finally, to identify further combinational options, we performed high-throughput drug screening and uncovered novel drug interactions with carfilzomib. For instance, cyclosporin A, a known immunosuppressive agent, enhanced carfilzomib's efficacy in vitro and in vivo. Altogether, these results demonstrate that carfilzomib and its combinations could be repurposed for LPS clinical management.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/20v22380Test

المؤلفون: Han, Lin, Madan, Vikas, Mayakonda, Anand, Dakle, Pushkar, Woon, Teoh, Shyamsunder, Pavithra, Nordin, Hazimah, Cao, Zeya, Sundaresan, Janani, Lei, Ienglam, Wang, Zhong, Koeffler, H

المصدر: Leukemia. 33(9)

مصطلحات موضوعية: Animals, Cell Differentiation, Cell Line, Tumor, Cell Lineage, Chromatin, Chromatin Assembly and Disassembly, DNA-Binding Proteins, Hematopoiesis, Humans, Mice, Mice, Inbred C57BL, Myeloid Cells, Transcription Factors

الوصف: Precise regulation of chromatin architecture is vital to physiological processes including hematopoiesis. ARID1A is a core component of the mammalian SWI/SNF complex, which is one of the ATP-dependent chromatin remodeling complexes. To uncover the role of ARID1A in hematopoietic development, we utilized hematopoietic cell-specific deletion of Arid1a in mice. We demonstrate that ARID1A is essential for maintaining the frequency and function of hematopoietic stem cells and its loss impairs the differentiation of both myeloid and lymphoid lineages. ARID1A deficiency led to a global reduction in open chromatin and ensuing transcriptional changes affected key genes involved in hematopoietic development. We also observed that silencing of ARID1A affected ATRA-induced differentiation of NB4 cells, suggesting its role in granulocytic differentiation of human leukemic cells. Overall, our study provides a comprehensive elucidation of the function of ARID1A in hematopoiesis and highlights the central role of ARID1A-containing SWI/SNF complex in maintaining chromatin dynamics in hematopoietic cells.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/0hm96912Test

المؤلفون: Madan, Vikas, Han, Lin, Hattori, Norimichi, Teoh, Weoi Woon, Mayakonda, Anand, Sun, Qiao-Yang, Ding, Ling-Wen, Nordin, Hazimah Binte Mohd, Lim, Su Lin, Shyamsunder, Pavithra, Dakle, Pushkar, Sundaresan, Janani, Doan, Ngan B, Sanada, Masashi, Sato-Otsubo, Aiko, Meggendorfer, Manja, Yang, Henry, Said, Jonathan W, Ogawa, Seishi, Haferlach, Torsten, Liang, Der-Cherng, Shih, Lee-Yung, Nakamaki, Tsuyoshi, Wang, Q Tian, Koeffler, H Phillip

المصدر: Haematologica. 103(12)

مصطلحات موضوعية: Rare Diseases, Human Genome, Childhood Leukemia, Cancer, Pediatric, Hematology, Pediatric Cancer, Genetics, 2.1 Biological and endogenous factors, Aetiology, Acute Disease, Animals, Cell Differentiation, Cell Proliferation, Gene Expression Profiling, Hematopoiesis, Humans, Leukemia, Myeloid, Mice, 129 Strain, Mice, Inbred C57BL, Mice, Knockout, Myeloid Cells, Myelopoiesis, Repressor Proteins, Immunology

الوصف: Chromosomal translocation t(8;21)(q22;q22) which leads to the generation of oncogenic RUNX1-RUNX1T1 (AML1-ETO) fusion is observed in approximately 10% of acute myelogenous leukemia (AML). To identify somatic mutations that co-operate with t(8;21)-driven leukemia, we performed whole and targeted exome sequencing of an Asian cohort at diagnosis and relapse. We identified high frequency of truncating alterations in ASXL2 along with recurrent mutations of KIT, TET2, MGA, FLT3, and DHX15 in this subtype of AML. To investigate in depth the role of ASXL2 in normal hematopoiesis, we utilized a mouse model of ASXL2 deficiency. Loss of ASXL2 caused progressive hematopoietic defects characterized by myeloid hyperplasia, splenomegaly, extramedullary hematopoiesis, and poor reconstitution ability in transplantation models. Parallel analyses of young and >1-year old Asxl2-deficient mice revealed age-dependent perturbations affecting, not only myeloid and erythroid differentiation, but also maturation of lymphoid cells. Overall, these findings establish a critical role for ASXL2 in maintaining steady state hematopoiesis, and provide insights into how its loss primes the expansion of myeloid cells.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/5j91t9wnTest

المؤلفون: Xu, Liang, Chen, Ye, Dutra-Clarke, Marina, Mayakonda, Anand, Hazawa, Masaharu, Savinoff, Steve E, Ngan, Doan, Said, Jonathan W, Yong, William H, Watkins, Ashley, Yang, Henry, Ding, Ling-Wen, Jiang, Yan-Yi, Tyner, Jeffrey W, Ching, Jianhong, Kovalik, Jean-Paul, Madan, Vikas, Chan, Shing-Leng, Muschen, Markus, Breunig, Joshua J, Lin, De-Chen, Koeffler, H Phillip

المصدر: Proceedings of the National Academy of Sciences of the United States of America. 114(21)

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/1nj2j1thTest

المؤلفون: Suh, Hyung C, Benoukraf, Touati, Shyamsunder, Pavithra, Yin, Tong, Cao, Qi, Said, Jonathan, Lee, Stephen, Lim, Ricky, Yang, Henry, Salotti, Jacqueline, Johnson, Peter F, Madan, Vikas, Koeffler, H Phillip

المصدر: Scientific reports. 7(1)

مصطلحات موضوعية: Granulocytes, Neutrophils, Bone Marrow Cells, Animals, Mice, Lipopolysaccharides, CCAAT-Enhancer-Binding Proteins, Cell Differentiation, Transcriptome, Triggering Receptor Expressed on Myeloid Cells-1

الوصف: C/EBPε is a critical transcriptional factor for granulocyte differentiation and function. Individuals with germline mutations of C/EBPε fail to develop normal granulocytes and suffer from repeated infections. In order to gain a global view of the transcriptional machinery regulated by C/EBPε, we performed whole-genome ChIP-Seq using mouse bone marrow cells. To complement the C/EBPε DNA binding analyses, RNA-Sequencing was done in parallel using sorted mature and immature granulocytes from WT and C/EBPε KO bone marrow. This approach led to the identification of several direct targets of C/EBPε, which are potential effectors of its role in granulocytic differentiation and function. Interestingly, Trem1, a gene critical to granulocyte function, was identified as a direct C/EBPε target gene. Trem1 expression overlaps very closely with expression signature of C/EBPε during hematopoietic development. Luciferase reporter and EMSA assays revealed that C/EBPε binds to the regulatory elements of Trem1 and regulates its expression during granulocytic differentiation. In addition, we provide evidence that inflammatory stimuli (LPS) can also control the expression of Trem1 independent of C/EBPε. Overall, this study provides comprehensive profiling of the transcriptional network controlled by C/EBPε during granulopoiesis and identifies Trem1 as one of its downstream effectors involved in eliciting an immune response.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/1h526612Test

المؤلفون: Xu, Liang, Chen, Ye, Dutra-Clarke, Marina, Mayakonda, Anand, Hazawa, Masaharu, Savinoff, Steve E, Doan, Ngan, Said, Jonathan W, Yong, William H, Watkins, Ashley, Yang, Henry, Ding, Ling-Wen, Jiang, Yan-Yi, Tyner, Jeffrey W, Ching, Jianhong, Kovalik, Jean-Paul, Madan, Vikas, Chan, Shing-Leng, Müschen, Markus, Breunig, Joshua J, Lin, De-Chen, Koeffler, H Phillip

المصدر: Proceedings of the National Academy of Sciences of the United States of America. 114(15)

مصطلحات موضوعية: Cell Line, Tumor, Animals, Humans, Mice, Mutant Strains, Glioma, Glioblastoma, Brain Neoplasms, Quinazolines, MAP Kinase Kinase Kinases, Receptor Protein-Tyrosine Kinases, Proto-Oncogene Proteins, Xenograft Model Antitumor Assays, Signal Transduction, Gene Expression Regulation, Neoplastic, Tumor Suppressor Protein p53, Proto-Oncogene Proteins c-bcl-6, Molecular Targeted Therapy, Gefitinib, Axl Receptor Tyrosine Kinase, AXL, BCL6, NCoR, ZBTB, glioblastoma multiforme, Cancer, Brain Cancer, Brain Disorders, Biotechnology, Neurosciences, Genetics, Rare Diseases

الوصف: ZBTB transcription factors orchestrate gene transcription during tissue development. However, their roles in glioblastoma (GBM) remain unexplored. Here, through a functional screening of ZBTB genes, we identify that BCL6 is required for GBM cell viability and that BCL6 overexpression is associated with worse prognosis. In a somatic transgenic mouse model, depletion of Bcl6 inhibits the progression of KrasG12V-driven high-grade glioma. Transcriptome analysis demonstrates the involvement of BCL6 in tumor protein p53 (TP53), erythroblastic leukemia viral oncogene homolog (ErbB), and MAPK signaling pathways. Indeed, BCL6 represses the expression of wild-type p53 and its target genes in GBM cells. Knockdown of BCL6 augments the activation of TP53 pathway in response to radiation. Importantly, we discover that receptor tyrosine kinase AXL is a transcriptional target of BCL6 in GBM and mediates partially the regulatory effects of BCL6 on both MEK-ERK (mitogen-activated protein/extracellular signal-regulated kinase kinase-extracellular signal-regulated kinase) and S6K-RPS6 (ribosomal protein S6 kinase-ribosomal protein S6) axes. Similar to BCL6 silencing, depletion of AXL profoundly attenuates GBM proliferation both in vitro and in vivo. Moreover, targeted inhibition of BCL6/nuclear receptor corepressor 1 (NCoR) complex by peptidomimetic inhibitor not only significantly decreases AXL expression and the activity of MEK-ERK and S6K-RPS6 cascades but also displays a potent antiproliferative effect against GBM cells. Together, these findings uncover a glioma-promoting role of BCL6 and provide the rationale of targeting BCL6 as a potential therapeutic approach.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/5j1863bmTest

المؤلفون: Ding, Ling-Wen, Sun, Qiao-Yang, Tan, Kar-Tong, Chien, Wenwen, Thippeswamy, Anand Mayakonda, Yeoh, Allen Eng Juh, Kawamata, Norihiko, Nagata, Yasunobu, Xiao, Jin-Fen, Loh, Xin-Yi, Lin, De-Chen, Garg, Manoj, Jiang, Yan-Yi, Xu, Liang, Lim, Su-Lin, Liu, Li-Zhen, Madan, Vikas, Sanada, Masashi, Fernández, Lucia Torres, Preethi, Hema, Lill, Michael, Kantarjian, Hagop M, Kornblau, Steven M, Miyano, Satoru, Liang, Der-Cherng, Ogawa, Seishi, Shih, Lee-Yung, Yang, Henry, Koeffler, H Phillip

المصدر: Cancer Research. 77(2)

مصطلحات موضوعية: Biological Sciences, Biomedical and Clinical Sciences, Genetics, Oncology and Carcinogenesis, Cancer, Rare Diseases, Clinical Research, Childhood Leukemia, Pediatric Research Initiative, Pediatric Cancer, Biotechnology, Hematology, Pediatric, Aetiology, 2.1 Biological and endogenous factors, Good Health and Well Being, Adolescent, Animals, Blotting, Western, Child, Child, Preschool, DNA Mutational Analysis, Female, High-Throughput Nucleotide Sequencing, Humans, Infant, Male, Mice, Mutation, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Oncology & Carcinogenesis, Biochemistry and cell biology, Oncology and carcinogenesis

الوصف: Current standard of care for patients with pediatric acute lymphoblastic leukemia (ALL) is mainly effective, with high remission rates after treatment. However, the genetic perturbations that give rise to this disease remain largely undefined, limiting the ability to address resistant tumors or develop less toxic targeted therapies. Here, we report the use of next-generation sequencing to interrogate the genetic and pathogenic mechanisms of 240 pediatric ALL cases with their matched remission samples. Commonly mutated genes fell into several categories, including RAS/receptor tyrosine kinases, epigenetic regulators, transcription factors involved in lineage commitment, and the p53/cell-cycle pathway. Unique recurrent mutational hotspots were observed in epigenetic regulators CREBBP (R1446C/H), WHSC1 (E1099K), and the tyrosine kinase FLT3 (K663R, N676K). The mutant WHSC1 was established as a gain-of-function oncogene, while the epigenetic regulator ARID1A and transcription factor CTCF were functionally identified as potential tumor suppressors. Analysis of 28 diagnosis/relapse trio patients plus 10 relapse cases revealed four evolutionary paths and uncovered the ordering of acquisition of mutations in these patients. This study provides a detailed mutational portrait of pediatric ALL and gives insights into the molecular pathogenesis of this disease. Cancer Res; 77(2); 390-400. ©2016 AACR.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/4rn1q1hbTest

المؤلفون: Madan, Vikas, Cao, Zeya, Teoh, Weoi Woon, Dakle, Pushkar, Han, Lin, Shyamsunder, Pavithra, Jeitany, Maya, Zhou, Siqin, Li, Jia, Hazimah Mohd Nordin, Shi, JiZhong, Yu, Shuizhou, Yang, Henry, Md Zakir Hossain, Chng, Wee Joo, Koeffler, H Phillip

المساهمون: School of Biological Sciences, Cancer Science Institute of Singapore, NUS

مصطلحات موضوعية: Science::Medicine, Protein P53, Hematopoietic Cell

الوصف: Recurrent loss-of-function mutations of spliceosome gene, ZRSR2, occur in myelodysplastic syndromes (MDS). Mutation/loss of ZRSR2 in human myeloid cells primarily causes impaired splicing of the U12-type introns. In order to further investigate the role of this splice factor in RNA splicing and hematopoietic development, we generated mice lacking ZRSR2. Unexpectedly, Zrsr2-deficient mice developed normal hematopoiesis with no abnormalities in myeloid differentiation evident in either young or ≥1-year old knockout mice. Repopulation ability of Zrsr2-deficient hematopoietic stem cells was also unaffected in both competitive and non-competitive reconstitution assays. Myeloid progenitors lacking ZRSR2 exhibited mis-splicing of U12-type introns, however, this phenotype was moderate compared to the ZRSR2-deficient human cells. Our investigations revealed that a closely related homolog, Zrsr1, expressed in the murine hematopoietic cells, but not in human cells contributes to splicing of U12-type introns. Depletion of Zrsr1 in Zrsr2 KO myeloid cells exacerbated retention of the U12-type introns, thus highlighting a collective role of ZRSR1 and ZRSR2 in murine U12-spliceosome. We also demonstrate that aberrant retention of U12-type introns of MAPK9 and MAPK14 leads to their reduced protein expression. Overall, our findings highlight that both ZRSR1 and ZRSR2 are functional components of the murine U12-spliceosome, and depletion of both proteins is required to accurately model ZRSR2-mutant MDS in mice. ; Ministry of Education (MOE) ; Ministry of Health (MOH) ; National Medical Research Council (NMRC) ; National Research Foundation (NRF) ; Published version ; This work was funded by the Leukemia and Lymphoma Society, the Singapore Ministry of Health’s National Medical Research Council (NMRC) under its Singapore Translational Research (STaR) Investigator Award to HPK (NMRC/STaR/0021/2014), the NMRC Center Grant awarded to the National University Cancer Institute of Singapore (NMRC/CG/012/2013) and the National Research ...

وصف الملف: application/pdf

العلاقة: NMRC/CG/012/2013; MOE2014-T3-1-006; Haematologica; Madan, V., Cao, Z., Teoh, W. W., Dakle, P., Han, L., Shyamsunder, P., Jeitany, M., Zhou, S., Li, J., Hazimah Mohd Nordin, Shi, J., Yu, S., Yang, H., Md Zakir Hossain, Chng, W. J. & Koeffler, H. P. (2022). ZRSR1 co-operates with ZRSR2 in regulating splicing of U12-type introns in murine hematopoietic cells. Haematologica, 107(3), 680-689. https://dx.doi.org/10.3324/haematol.2020.260562Test; https://hdl.handle.net/10356/162693Test; 2-s2.0-85125553217; 107; 680; 689

الإتاحة: https://doi.org/10.3324/haematol.2020.260562Test
https://hdl.handle.net/10356/162693Test