CoChat
Sign Up
PreprintCited by 31Acute Myeloid Leukemia ResearchGenomics and Chromatin DynamicsChromatin Remodeling and Cancer

The DOI matches its Crossref record; 1 of the 1 references it cites were found in a registry or an index.

A distinct core regulatory module enforces oncogene expression in KMT2A-rearranged leukemia

Open access
Harada, Taku, Heshmati, Yaser, Kalfon, Jérémie, Ferrucio, Juliana Xavier, Perez, Monika, Ewers, Jazmin, Kossenkov, Andrew, Ellegast, Jana M., Yi, Joanna S., Bowker, Allyson, Zhu, Qian, Eagle, Kenneth, Dempster, Joshua M., Kugener, Guillaume, Wickramasinghe, Jayamanna, Herbert, Zachary T., Li, Charles H., Koren, Jošt Vrabič, Weinstock, David M., Paralkar, Vikram R., Nabet, Behnam, Lin, Charles Y., Dharia, Neekesh V., Stegmaier, Kimberly, Orkin, Stuart H., Pimkin, Maxim·2021·Genes & Development
DOI 10.1101/2021.08.03.454902PMC PMC8973843

Preprint — published as 10.1101/gad.349284.121

Open this paper in CoChat — free accountOpen PDF

Abstract

Summary: A small set of lineage-restricted transcription factors (TFs), termed core regulatory circuitry (CRC), control cell identity and malignant transformation. Here, we integrated gene dependency, chromatin architecture and TF perturbation datasets to characterize 31 core TFs in acute myeloid leukemia (AML). Contrary to a widely accepted model, we detected a modular CRC structure with hierarchically organized, partially redundant and only sparsely interconnected modules of core TFs controlling distinct genetic programs. Rapid TF degradation followed by measurement of genome-wide transcription rates revealed that core TFs directly regulate dramatically fewer genes than previously assumed. Leukemias carrying KMT2A (MLL) rearrangements depend on the IRF8/MEF2 axis to directly enforce expression of the key oncogenes MYC, HOXA9 and BCL2. Our datasets provide an evolving model of CRC organization in human cells, and a resource for further inquiries into and therapeutic targeting of aberrant transcriptional circuits in cancer.

Overview

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1101/2021.08.03.454902

Cites

1 of 1 references verified0 citation errors · 0 not checkable

Statistics

Verification

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Citations

Cites

Flagged first, then by citations

Research works printed but not linked: 130

  1. 10.1016/j.cell.2012.04.040 · DOI · Paper page
  2. 10.1016/j.devcel.2012.09.003 · DOI
  3. 10.1084/jem.20102260 · DOI · Paper page
  4. 10.1016/j.cell.2011.01.004 · DOI · Paper page
  5. 10.1016/j.cell.2006.07.024 · DOI · Paper page
  6. 10.1038/nature08533 · DOI · Paper page
  7. 10.1016/0092-8674(87)90585-X · DOI
  8. 10.1016/j.cell.2011.05.019 · DOI
  9. 10.1016/j.cell.2005.08.020 · DOI · Paper page
  10. 10.1101/gr.197590.115 · DOI
  11. 10.1016/j.cell.2013.02.014 · DOI
  12. 10.1038/s41588-018-0191-z · DOI
  13. 10.1038/ng.3167 · DOI
  14. 10.1016/j.cell.2013.03.035 · DOI · Paper page
  15. 10.1016/j.molcel.2015.02.014 · DOI · Paper page
  16. 10.1016/j.cell.2013.09.053 · DOI · Paper page
  17. 10.1126/science.1259037 · DOI · Paper page
  18. 10.1084/jem.20190196 · DOI
  19. 2017, Heterogeneity of neuroblastoma cell identity defined by transcriptional circuitries, Nat Genet, 2, 16078
  20. 10.1038/ng.3899 · DOI
  21. 10.1038/nature16546 · DOI
  22. 10.1038/nature25169 · DOI
  23. 10.1016/j.ccr.2013.11.003 · DOI · Paper page
  24. 10.1158/2159-8290.CD-17-0399 · DOI
  25. 10.1016/j.cell.2016.12.013 · DOI
  26. 2019, Targeting transcription factors in cancer — from undruggable to reality, Nat Rev Cancer, 19, 611, 10.1038/s41568-019-0196-7 · DOI · Paper page
  27. 10.1038/s41586-018-0623-z · DOI
  28. 2020, A compendium of mutational cancer driver genes, Nat Rev Cancer, 20, 555, 10.1038/s41568-020-0290-x · DOI
  29. 10.1016/j.ccell.2018.10.015 · DOI
  30. 2017, Super-Enhancer-Driven Transcriptional Dependencies in Cancer, Trends in cancer, 3, 269, 10.1016/j.trecan.2017.03.006 · DOI
  31. 10.1016/j.cell.2017.07.007 · DOI
  32. 10.1016/j.cell.2013.03.036 · DOI · Paper page
  33. 10.1038/ng.3646 · DOI · Paper page
  34. 10.1182/blood-2011-04-347872 · DOI
  35. 10.1016/S0140-6736(12)61727-9 · DOI
  36. 10.1038/nri2024 · DOI · Paper page
  37. 10.7554/elife.65905 · DOI
  38. 10.1056/NEJMoa1301689 · DOI · Paper page
  39. 10.1038/nm.4439 · DOI
  40. 2015, Proxe: A Public Repository of Xenografts to Facilitate Studies of Biology and Expedite Preclinical Drug Development in Leukemia and Lymphoma, Blood, 126, 3252, 10.1182/blood.V126.23.3252.3252 · DOI
  41. 10.1038/nmeth.3999 · DOI · Paper page
  42. 10.1038/s41588-019-0538-0 · DOI · Paper page
  43. 10.1038/s41592-018-0048-5 · DOI
  44. 10.1038/463858a · DOI
  45. 2021, A first-generation pediatric cancer dependency map, Nat Genet, 53, 529, 10.1038/s41588-021-00819-w · DOI · Paper page
  46. 2021, Global computational alignment of tumor and cell line transcriptional profiles, Nat Commun, 12, 22, 10.1038/s41467-020-20294-x · DOI
  47. 10.1038/ng.3967 · DOI · Paper page
  48. 10.1038/s41568-018-0095-3 · DOI
  49. 10.1016/j.ccell.2018.11.001 · DOI
  50. 10.1038/s41588-019-0534-4 · DOI
  51. 2019, Extracting Biological Insights from the Project Achilles Genome-Scale CRISPR Screens in Cancer Cell Lines, Biorxiv, 20, 720243
  52. 10.1038/ng.3984 · DOI · Paper page
  53. 10.1158/2159-8290.CD-16-0154 · DOI
  54. 10.1016/j.cell.2017.07.005 · DOI · Paper page
  55. 10.1016/j.molcel.2018.02.011 · DOI
  56. 10.1182/blood.2019001576 · DOI
  57. 10.1158/2159-8290.CD-17-1271 · DOI
  58. 10.1038/nature04980 · DOI · Paper page
  59. 2018, Paediatric patients with acute leukaemia and KMT2A (MLL) rearrangement show a distinctive expression pattern of histone deacetylases, Brit J Haematol, 182, 542, 10.1111/bjh.15436 · DOI
  60. 2017, MLL-AF4 Spreading Identifies Binding Sites that Are Distinct from Super-Enhancers and that Govern Sensitivity to DOT1L Inhibition in Leukemia, Cell Reports, 18, 482, 10.1016/j.celrep.2016.12.054 · DOI
  61. 10.1182/blood-2013-02-485771 · DOI
  62. 10.1038/ng765 · DOI
  63. 10.1182/blood-2004-03-1154 · DOI
  64. 10.1172/JCI33255 · DOI
  65. E. C. Partridge , S. B. Chhetri , J. W. Prokop , R. C. Ramaker , C. S. Jansen , S.-T. Goh , M. Mackiewicz , K. M. Newberry , L. A. Brandsmeier , S. K. Meadows , C. L. Messer , A. A. Hardigan , C. J. Coppola , E. C. Dean , S. Jiang , D. Savic , A. Mortazavi , B. J. Wold , R. M. Myers , E. M. Mendenhall , Occupancy maps of 208 chromatin-associated proteins in one human cell type. Nature, 1–40 (2020). · DOI · Paper page
  66. 10.1016/j.tibs.2014.07.002 · DOI · Paper page
  67. 2015, The Overlooked Fact: Fundamental Need for Spike-In Control for Virtually All Genome-Wide Analyses, Molecular and cellular biology, 36, 662
  68. 10.1016/j.cell.2012.10.012 · DOI · Paper page
  69. 10.1016/S1047-8477(02)00514-2 · DOI
  70. 2019, Direct Inhibition of IRF-Dependent Transcriptional Regulatory Mechanisms Associated With Disease, Front Immunol, 10, 1176, 10.3389/fimmu.2019.01176 · DOI
  71. 10.1128/MCB.19.4.3051 · DOI
  72. 10.1158/1538-7445.AM2012-3119 · DOI
  73. 10.1016/j.stem.2010.07.016 · DOI · Paper page
  74. 10.1182/blood-2012-09-458570 · DOI
  75. 10.1097/MOH.0000000000000245 · DOI
  76. 2019, Direct and Indirect Targeting of HOXA9 Transcription Factor in Acute Myeloid Leukemia, Cancers, 11, 837, 10.3390/cancers11060837 · DOI
  77. 2018, HOXA9 Reprograms the Enhancer Landscape to Promote Leukemogenesis, Cancer Cell, 34, 643, 10.1016/j.ccell.2018.08.018 · DOI · Paper page
  78. 10.1038/nrg.2016.118 · DOI
  79. 2018, The dTAG system for immediate and target-specific protein degradation, Nat Chem Biol, 14, 1
  80. 2020, Rapid and direct control of target protein levels with VHL-recruiting dTAG molecules, Nature communications, 11, 4687, 10.1038/s41467-020-18377-w · DOI · Paper page
  81. 10.1126/science.aao2793 · DOI
  82. 10.1038/nmeth.4435 · DOI · Paper page
  83. 10.1016/j.cell.2012.08.033 · DOI
  84. 10.1016/j.cell.2012.08.026 · DOI
  85. 2020, Targeting Bcl-2 Proteins in Acute Myeloid Leukemia, Frontiers Oncol, 10, 584974, 10.3389/fonc.2020.584974 · DOI
  86. 10.1038/nature14904 · DOI
  87. 2018, Peptidomimetic blockade of MYB in acute myeloid leukemia, Nat Commun, 9, 110, 10.1038/s41467-017-02618-6 · DOI
  88. 2019, Targeting chromatin complexes in fusion protein-driven malignancies, Nat Rev Cancer, 19, 1
  89. 10.1016/j.exphem.2015.05.012 · DOI
  90. 10.1158/2643-3230.bcd-20-0105 · DOI
  91. 10.1126/science.1244851 · DOI · Paper page
  92. 10.1182/blood-2016-05-714493 · DOI
  93. 10.1038/onc.2015.174 · DOI
  94. 10.1182/blood-2007-09-113597 · DOI
  95. B. Verd , N. A. Monk , J. Jaeger , Modularity, criticality, and evolvability of a developmental gene regulatory network. 13, 20160179–37 (2018). · DOI
  96. 10.1038/nrg2267 · DOI
  97. 2019, Chromatin Environment and Cellular Context Specify Compensatory Activity of Paralogous MEF2 Transcription Factors, Cell Reports, 29, 2001, 10.1016/j.celrep.2019.10.033 · DOI
  98. 10.1073/pnas.2019655118 · DOI
  99. 10.1126/science.aag1550 · DOI
  100. Y. Chen , L. Xu , R. Y.-T. Lin , M. Muschen , H. P. Koeffler , Core transcriptional regulatory circuitries in cancer. Oncogene, 1–14 (2020). · DOI
  101. 10.1016/j.cell.2015.04.014 · DOI
  102. 10.1016/0092-8674(75)90116-6 · DOI · Paper page
  103. 10.1101/gr.097378.109 · DOI
  104. 10.1101/gad.1561707 · DOI · Paper page
  105. 10.1056/NEJMoa1516192 · DOI · Paper page
  106. 10.1016/j.cell.2017.02.007 · DOI · Paper page
  107. 2021, Biomolecular condensates and cancer, Cancer Cell, 39, 174, 10.1016/j.ccell.2020.12.003 · DOI
  108. 2020, Biomolecular Condensates in the Nucleus, Trends in biochemical sciences, 45, 961, 10.1016/j.tibs.2020.06.007 · DOI
  109. 2018, Coactivator condensation at super-enhancers links phase separation and gene control, Science, 19, eaar3958
  110. 10.1016/j.molcel.2019.08.016 · DOI
  111. 10.1016/j.cell.2018.10.042 · DOI · Paper page
  112. 10.1038/nrm.2017.7 · DOI
  113. 10.1242/dev.182766 · DOI
  114. 10.1016/j.cell.2018.10.057 · DOI · Paper page
  115. 2018, Phase separation and gene control, Science (New York, N.Y.), 361, 375
  116. 2018, Systematic analysis of protein turnover in primary cells, Nature communications, 9, 689, 10.1038/s41467-018-03106-1 · DOI
  117. 10.1016/j.cell.2012.03.003 · DOI · Paper page
  118. 10.1186/s13045-015-0215-4 · DOI
  119. 10.1126/science.286.5439.531 · DOI · Paper page
  120. 10.1038/leu.2008.198 · DOI
  121. 10.1073/pnas.1402238111 · DOI
  122. 2015, MEF2B mutations in non-Hodgkin lymphoma dysregulate cell migration by decreasing MEF2B target gene activation, Nature communications, 6, 7953, 10.1038/ncomms8953 · DOI
  123. 10.1182/blood-2008-05-158196 · DOI
  124. 10.1093/nar/gkw377 · DOI · Paper page
  125. 2020, BCL11A enhancer–edited hematopoietic stem cells persist in rhesus monkeys without toxicity, Journal of Clinical Investigation, 130, 6677, 10.1172/JCI140189 · DOI
  126. 10.1182/blood-2016-01-693705 · DOI
  127. 10.1101/gr.136184.111 · DOI · Paper page
  128. 10.1371/journal.pone.0166438 · DOI
  129. 10.1016/j.cell.2017.11.008 · DOI · Paper page
  130. 10.1016/j.molcel.2014.08.024 · DOI · Paper page

Metadata

Authors
Harada, T., Heshmati, Y., Kalfon, J., Ferrucio, J. X., Perez, M., Ewers, J., Kossenkov, A., Ellegast, J. M., Yi, J. S., Bowker, A., Zhu, Q., Eagle, K., Dempster, J. M., Kugener, G., Wickramasinghe, J., Herbert, Z. T., Li, C. H., Koren, J. V., Weinstock, D. M., Paralkar, V. R., Nabet, B., Lin, C. Y., Dharia, N. V., Stegmaier, K., Orkin, S. H., & Pimkin, M.
Affiliations
  • Boston Children's Hospital (US)
  • Broad Institute (US)
  • The Wistar Institute (US)
  • Baylor College of Medicine (US)
  • Harvard University (US)
  • Whitehead Institute for Biomedical Research (US)
  • University of Pennsylvania (US)
  • Fred Hutch Cancer Center (US)
ORCID
Venue
Genes & Development
Publisher
openRxiv
Published
2021-08-04
Volume
36
Issue
5-6
Pages
368-389
ISSN
0890-9369 (ISSN-L)
DOI
10.1101/2021.08.03.454902
PMC
PMC8973843
OpenAlex
W4220938601
Cited by
31
References
1
Citations by year
2026: 9 · 2025: 6 · 2024: 3 · 2023: 10 · 2022: 3
Type
posted content
Language
en
Open access
Licence
cc-by
Locations
  • Genes & Development (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • National Science Foundation
  • Children's Cancer Research Fund
  • Pediatric Cancer Research Foundation
  • Damon Runyon Cancer Research Foundation
  • Alex's Lemonade Stand Foundation for Childhood Cancer
  • Lady Tata Memorial Trust
  • Curing Kids Cancer
  • Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
  • National Institutes of Health (NIH P50, 5r01hl155144-04, CA206963)
  • National Heart, Lung, and Blood Institute (R01-HL155144)
  • National Cancer Institute (P50CA206963, R35CA210030, R50CA211199, P30CA010815)
  • Hyundai Hope On Wheels
  • When Everyone Survives Foundation
Topics
  • Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
Keywords
MLL rearrangement, MLL-rearranged acute myeloid leukemia, MEF2D, IRF8, MEF2C, transcriptional addiction, oncogene expression, c-Myc, HOXA9, Bcl-2, transcription factor degradation, enhancer architecture, transcriptional dependency
MeSH terms
Humans, Oncogenes, Gene Rearrangement, Leukemia, Myeloid, Acute, Interferon Regulatory Factors, Myeloid-Lymphoid Leukemia Protein

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review