Differentiation block in acute myeloid leukemia regulated by intronic sequences of .

Iroquois transcription factor gene is highly expressed in 20-30% of acute myeloid leukemia (AML) and contributes to the pathognomonic differentiation block. Intron 8 sequences ∼220kB downstream of exhibit histone acetylation, DNA methylation, and contacts with the promoter, which correlate with expression. Deletion of these intronic elements confirms a role in positively regulating . RNAseq revealed long non-coding (lnc) transcripts arising from this locus. -lncAML knockdown (KD) induced differentiation of AML cells, loss of clonogenic activity, and reduced intron 8: promoter contacts. While both -lncAML KD and KD induced differentiation, -lncAML but not KD led to HOXA downregulation suggesting transcript activity . -lncAML AML samples expressed higher levels of HOXA and lower levels of differentiation genes. Thus, a regulatory module in intron 8 consisting of clustered enhancer elements and a long non-coding RNA is active in human AML, impeding myeloid differentiation.