Subtype-specific regulatory network rewiring in acute myeloid leukemia

Abstract

Acute myeloid leukemia (AML) is a heterogeneous disease caused by a variety of mutations in transcription factors, epigenetic regulators and signaling molecules. To determine how different mutant regulators establish AML subtype-specific transcriptional networks we performed a comprehensive global analysis of cis-regulatory element activity and interaction, transcription factor occupancy and gene expression patterns in purified leukemic blast cells. Here, we focussed on specific sub-groups of patients carrying mutations in genes encoding transcription factors ( RUNX1, CEBPA) and signaling molecules ( FTL3-ITD, RAS, NPM1). Integrated analyses of these data demonstrates that each mutant regulator establishes a specific transcriptional and signaling network unrelated to that seen in normal cells, sustaining the expression of unique sets of genes required for AML growth and maintenance.

Transcriptional networks in acute myeloid leukemia

“…112 Perhaps surprisingly, all three AML subtypes also had similar genome-wide patterns of H3K9/K14 acetylation, suggesting that while these three fusion genes bind distinct genomic locations they may have similar effects on global chromatin organization and therefore on the architecture of transcriptional networks. 112 Similarly, Assi et al found that RUNX1-RUNX1T, CBFB-MYH11, and CEBPA mutations target a common set of target genes, 66 further emphasizing that diverse genomic aberrations converge on the same target genes in AML.…”

“…Mutation‐mediated loss of RUNX1 function may impact on myeloid differentiation since RUNX1 is known to regulate CEBPA through binding to the CEBPA +37 enhancer and also directly regulates SPI1 . RUNX1 ‐mutated AMLs also cluster together based on global chromatin accessibility, suggesting that mutationally altered RUNX1 function is able to impact the global cis ‐regulatory landscape . Surprisingly, RUNX1 is overexpressed in AMLs harboring FLT3 ‐ITD, and inactivating RUNX1 in this context leads to differentiation …”

“…FLT3 ‐ITD AMLs have distinct expression profiles compared to HSPCs and FLT3 wild‐type AMLs, and CEBPA and PU.1 are repressed . FLT3 ‐ITD AMLs also have distinct global accessible chromatin profiles, with the ITD‐specific accessible regions being enriched for RUNX, AP‐1, ETS, E‐box, and CEBP motifs, and bound RUNX1 . FLT3 ‐ITD signaling through the MAPK pathway leads to activation of AP‐1, which cooperates with RUNX1 to remodel chromatin and activate specific genes .…”

“…Assi et al used digital DNaseI footprinting and promoter capture HiC to survey genome‐wide changes in chromatin organization and found that AMLs with a range of molecular lesions had specific global patterns of chromatin accessibility that were distinct from normal HSPCs . Two major patterns of chromatin accessibility were identified, defined by (a) FLT3 ITD and NPM1 and (b) RUNX1/CBFB and CEBPA . Perhaps surprisingly, mutations in epigenetic regulators such as DNMT3A, TET2, or IDH did not show a major impact on global patterns of gene activation .…”

“…73 RUNX1-mutated AMLs also cluster together based on global chromatin accessibility, suggesting that mutationally altered RUNX1 function is able to impact the global cis-regulatory landscape. 66 Surprisingly, RUNX1 is overexpressed in AMLs harboring FLT3-ITD, and inactivating RUNX1 in this context leads to differentiation. 74…”