Enhancer remodeling drives MLL oncogene-dependent transcriptional dysregulation in leukemia stem cells

Blood Advances - Tập 7 - Trang 2504-2519 - 2023
Feng Pan1, Masayuki Iwasaki1,2, Wenqi Wu3, Yanan Jiang3, Xin Yang1, Li Zhu1, Zhigang Zhao3, Michael L. Cleary1
1Department of Pathology, Stanford University, Stanford, CA
2Department of Advanced Health Science, Institute of Laboratory Animals, Tokyo Women's Medical University, Tokyo, Japan
3Department of Hematology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, People’s Republic of China

Tóm tắt

Abstract Acute myeloid leukemia (AML) with mixed-lineage leukemia (MLL) gene rearrangement (MLLr) comprises a cellular hierarchy in which a subpopulation of cells serves as functional leukemia stem cells (LSCs). They are maintained by a unique gene expression program and chromatin states, which are thought to reflect the actions of enhancers. Here, we delineate the active enhancer landscape and observe pervasive enhancer malfunction in LSCs. Reconstruction of regulatory networks revealed a master set of hematopoietic transcription factors. We show that EP300 is an essential transcriptional coregulator for maintaining LSC oncogenic potential because it controls essential gene expression through modulation of H3K27 acetylation and assessments of transcription factor dependencies. Moreover, the EP300 inhibitor A-485 affects LSC growth by targeting enhancer activity via histone acetyltransferase domain inhibition. Together, these data implicate a perturbed MLLr-specific enhancer accessibility landscape, suggesting the possibility for disruption of the LSC enhancer regulatory axis as a promising therapeutic strategy in AML.

Tài liệu tham khảo

Tsai, 2017, Epigenetic therapies by targeting aberrant histone methylome in AML: molecular mechanisms, current preclinical and clinical development, Oncogene, 36, 1753, 10.1038/onc.2016.315 Krivtsov, 2007, MLL translocations, histone modifications and leukaemia stem-cell development, Nat Rev Cancer, 7, 823, 10.1038/nrc2253 Liedtke, 2009, Therapeutic targeting of MLL, Blood, 113, 6061, 10.1182/blood-2008-12-197061 Krivtsov, 2008, H3K79 methylation profiles define murine and human MLL-AF4 leukemias, Cancer Cell, 14, 355, 10.1016/j.ccr.2008.10.001 Somervaille, 2009, Hierarchical maintenance of MLL myeloid leukemia stem cells employs a transcriptional program shared with embryonic rather than adult stem cells, Cell Stem Cell, 4, 129, 10.1016/j.stem.2008.11.015 Meyer, 2018, The MLL recombinome of acute leukemias in 2017, Leukemia, 32, 273, 10.1038/leu.2017.213 Iwasaki, 2015, CD93 marks a non-quiescent human leukemia stem cell population and is required for development of MLL-rearranged acute myeloid leukemia, Cell Stem Cell, 17, 412, 10.1016/j.stem.2015.08.008 Somervaille, 2006, Identification and characterization of leukemia stem cells in murine MLL-AF9 acute myeloid leukemia, Cancer Cell, 10, 257, 10.1016/j.ccr.2006.08.020 Krivtsov, 2006, Transformation from committed progenitor to leukaemia stem cell initiated by MLL-AF9, Nature, 442, 818, 10.1038/nature04980 Long, 2016, Ever-changing landscapes: transcriptional enhancers in development and evolution, Cell, 167, 1170, 10.1016/j.cell.2016.09.018 Sur, 2016, The role of enhancers in cancer, Nat Rev Cancer, 16, 483, 10.1038/nrc.2016.62 Calo, 2013, Modification of enhancer chromatin: what, how, and why?, Mol Cell, 49, 825, 10.1016/j.molcel.2013.01.038 Yang, 2016, DNMT3A loss drives enhancer hypomethylation in FLT3-ITD-associated leukemias, Cancer Cell, 30, 363, 10.1016/j.ccell.2016.07.015 Bahr, 2018, A Myc enhancer cluster regulates normal and leukaemic haematopoietic stem cell hierarchies, Nature, 553, 515, 10.1038/nature25193 McKeown, 2017, Superenhancer analysis defines novel epigenomic subtypes of non-APL AML, including an RARalpha dependency targetable by SY-1425, a potent and selective RARalpha agonist, Cancer Discov, 7, 1136, 10.1158/2159-8290.CD-17-0399 Wong, 2015, The H3K4-methyl epigenome regulates leukemia stem cell oncogenic potential, Cancer Cell, 28, 198, 10.1016/j.ccell.2015.06.003 Jeong, 2019, High-efficiency CRISPR induction of t(9;11) chromosomal translocations and acute leukemias in human blood stem cells, Blood Adv, 3, 2825, 10.1182/bloodadvances.2019000450 Lara-Astiaso, 2014, Immunogenetics. Chromatin state dynamics during blood formation, Science, 345, 943, 10.1126/science.1256271 Li, 2009, Fast and accurate short read alignment with Burrows–Wheeler transform, bioinformatics, 25, 1754, 10.1093/bioinformatics/btp324 Zhang, 2008, Model-based analysis of ChIP-Seq (MACS), Genome biology, 9, 1, 10.1186/gb-2008-9-9-r137 Ernst, 2012, ChromHMM: automating chromatin-state discovery and characterization, Nat Methods, 9, 215, 10.1038/nmeth.1906 McLean, 2010, GREAT improves functional interpretation of cis-regulatory regions, Nat Biotechnol, 28, 495, 10.1038/nbt.1630 Ramirez, 2016, deepTools2: a next generation web server for deep-sequencing data analysis, Nucleic Acids Res, 44, W160, 10.1093/nar/gkw257 Shen, 2014, ngs.plot: quick mining and visualization of next-generation sequencing data by integrating genomic databases, BMC Genomics, 15, 284, 10.1186/1471-2164-15-284 Whyte, 2013, Master transcription factors and mediator establish super-enhancers at key cell identity genes, Cell, 153, 307, 10.1016/j.cell.2013.03.035 Heinz, 2010, Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities, Mol Cell, 38, 576, 10.1016/j.molcel.2010.05.004 Szklarczyk, 2019, STRING v11: protein–protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets, Nucleic acids research, 47, D607, 10.1093/nar/gky1131 Dobin, 2013, STAR: ultrafast universal RNA-seq aligner, Bioinformatics, 29, 15, 10.1093/bioinformatics/bts635 Ge, 2018, iDEP: an integrated web application for differential expression and pathway analysis of RNA-Seq data, BMC Bioinformatics, 19, 534, 10.1186/s12859-018-2486-6 Love, 2014, Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2, Genome Biol, 15, 550, 10.1186/s13059-014-0550-8 Wang, 2017, WebGestalt 2017: a more comprehensive, powerful, flexible and interactive gene set enrichment analysis toolkit, Nucleic Acids Res, 45, W130, 10.1093/nar/gkx356 Subramanian, 2005, Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles, Proc Natl Acad Sci U S A, 102, 15545, 10.1073/pnas.0506580102 Prange, 2017, MLL-AF9 and MLL-AF4 oncofusion proteins bind a distinct enhancer repertoire and target the RUNX1 program in 11q23 acute myeloid leukemia, Oncogene, 36, 3346, 10.1038/onc.2016.488 Sun, 2018, HOXA9 reprograms the enhancer landscape to promote leukemogenesis, Cancer Cell, 34, 643, 10.1016/j.ccell.2018.08.018 Local, 2018, Identification of H3K4me1-associated proteins at mammalian enhancers, Nat Genet, 50, 73, 10.1038/s41588-017-0015-6 Dorighi, 2017, Mll3 and Mll4 facilitate enhancer RNA synthesis and transcription from promoters independently of H3K4 monomethylation, Mol Cell, 66, 568, 10.1016/j.molcel.2017.04.018 Sondka, 2018, The COSMIC Cancer Gene Census: describing genetic dysfunction across all human cancers, Nat Rev Cancer, 18, 696, 10.1038/s41568-018-0060-1 Liu, 2017, ONGene: A literature-based database for human oncogenes, J Genet Genomics, 44, 119, 10.1016/j.jgg.2016.12.004 Pinto, 2015, StemChecker: a web-based tool to discover and explore stemness signatures in gene sets, Nucleic Acids Res, 43, W72, 10.1093/nar/gkv529 Medvedeva, 2015, EpiFactors: a comprehensive database of human epigenetic factors and complexes, Database (Oxford), 2015, bav067, 10.1093/database/bav067 Han, 2018, TRRUST v2: an expanded reference database of human and mouse transcriptional regulatory interactions, Nucleic Acids Res, 46, D380, 10.1093/nar/gkx1013 Bagger, 2019, BloodSpot: a database of healthy and malignant haematopoiesis updated with purified and single cell mRNA sequencing profiles, Nucleic Acids Res, 47, D881, 10.1093/nar/gky1076 Jin, 2011, Distinct roles of GCN5/PCAF-mediated H3K9ac and CBP/p300-mediated H3K18/27ac in nuclear receptor transactivation, EMBO J, 30, 249, 10.1038/emboj.2010.318 Tang, 2017, GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses, Nucleic Acids Res, 45, W98, 10.1093/nar/gkx247 Meyers, 2017, Computational correction of copy number effect improves specificity of CRISPR-Cas9 essentiality screens in cancer cells, Nat Genet, 49, 1779, 10.1038/ng.3984 Lasko, 2017, Discovery of a selective catalytic p300/CBP inhibitor that targets lineage-specific tumours, Nature, 550, 128, 10.1038/nature24028 Bhagwat, 2018, Enhancer dysfunction in leukemia, Blood, 131, 1795, 10.1182/blood-2017-11-737379 Cao, 2018, An Mll4/COMPASS-Lsd1 epigenetic axis governs enhancer function and pluripotency transition in embryonic stem cells, Sci Adv, 4, eaap8747, 10.1126/sciadv.aap8747 Mumbach, 2017, Enhancer connectome in primary human cells identifies target genes of disease-associated DNA elements, Nat Genet, 49, 1602, 10.1038/ng.3963 Wang, 2022, CBP/p300 and HDAC activities regulate H3K27 acetylation dynamics and zygotic genome activation in mouse preimplantation embryos, EMBO J, 41, e112012, 10.15252/embj.2022112012 Gregoricchio, 2022, HDAC1 and PRC2 mediate combinatorial control in SPI1/PU.1-dependent gene repression in murine erythroleukaemia, Nucleic Acids Res, 50, 7938, 10.1093/nar/gkac613 Picaud, 2015, Generation of a selective small molecule inhibitor of the CBP/p300 bromodomain for leukemia therapy, Cancer Res, 75, 5106, 10.1158/0008-5472.CAN-15-0236 Diesch, 2021, Inhibition of CBP synergizes with the RNA-dependent mechanisms of azacitidine by limiting protein synthesis, Nat Commun, 12, 6060, 10.1038/s41467-021-26258-z Daigle, 2011, Selective killing of mixed lineage leukemia cells by a potent small-molecule DOT1L inhibitor, Cancer Cell, 20, 53, 10.1016/j.ccr.2011.06.009 Yokoyama, 2005, The menin tumor suppressor protein is an essential oncogenic cofactor for MLL-associated leukemogenesis, Cell, 123, 207, 10.1016/j.cell.2005.09.025 Ishikawa, 2007, Chemotherapy-resistant human AML stem cells home to and engraft within the bone-marrow endosteal region, Nat Biotechnol, 25, 1315, 10.1038/nbt1350 Pollyea, 2014, Targeting acute myeloid leukemia stem cells: a review and principles for the development of clinical trials, Haematologica, 99, 1277, 10.3324/haematol.2013.085209