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

Genes Dev. 2022 Mar 1;36(5-6):368-389. doi: 10.1101/gad.349284.121. Epub 2022 Mar 17.


Acute myeloid leukemia with KMT2A (MLL) rearrangements is characterized by specific patterns of gene expression and enhancer architecture, implying unique core transcriptional regulatory circuitry. Here, we identified the transcription factors MEF2D and IRF8 as selective transcriptional dependencies of KMT2A-rearranged AML, where MEF2D displays partially redundant functions with its paralog, MEF2C. Rapid transcription factor degradation followed by measurements of genome-wide transcription rates and superresolution microscopy revealed that MEF2D and IRF8 form a distinct core regulatory module with a narrow direct transcriptional program that includes activation of the key oncogenes MYC, HOXA9, and BCL2. Our study illustrates a mechanism of context-specific transcriptional addiction whereby a specific AML subclass depends on a highly specialized core regulatory module to directly enforce expression of common leukemia oncogenes.

Keywords: IRF8; KMT2A-rearranged AML; MEF2D; transcriptional addiction.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Gene Rearrangement
  • Humans
  • Interferon Regulatory Factors / genetics
  • Interferon Regulatory Factors / metabolism
  • Leukemia, Myeloid, Acute* / genetics
  • Myeloid-Lymphoid Leukemia Protein* / genetics
  • Myeloid-Lymphoid Leukemia Protein* / metabolism
  • Oncogenes / genetics


  • Interferon Regulatory Factors
  • Myeloid-Lymphoid Leukemia Protein