Abstract
MLL-rearranged leukemia depends on H3K79 methylation. Depletion of this transcriptionally activating mark by DOT1L deletion or high concentrations of the inhibitor pinometostat downregulates HOXA9 and MEIS1, and consequently reduces leukemia survival. Yet, some MLL-rearranged leukemias are inexplicably susceptible to low-dose pinometostat, far below concentrations that downregulate this canonical proliferation pathway. In this context, we define alternative proliferation pathways that more directly derive from H3K79me2 loss. By ICeChIP-seq, H3K79me2 is markedly depleted at pinometostat-downregulated and MLL-fusion targets, with paradoxical increases of H3K4me3 and loss of H3K27me3. Although downregulation of polycomb components accounts for some of the proliferation defect, transcriptional downregulation of FLT3 is the major pathway. Loss-of-FLT3-function recapitulates the cytotoxicity and gene expression consequences of low-dose pinometostat, whereas overexpression of constitutively active STAT5A, a target of FLT3-ITD-signaling, largely rescues these defects. This pathway also depends on MLL1, indicating combinations of DOT1L, MLL1 and FLT3 inhibitors should be explored for treating FLT3-mutant leukemia.
Highlights
MLL1-rearrangements (MLL-r) account for ~10% of all leukemia cases and are especially prominent in infants (70-80%) and, lacking an effective standard of care, bear a very poor prognosis1–5
Little is known about why MLL-r leukemia cell lines have such disparate sensitivities to DOT1L inhibitors or how MLL-fusions might cooperate with co-occurring lesions
By investigating the effects of a DOT1L inhibitor at a low, as yet unexplored concentration, we revealed that MLL-r cell lines carrying FMS-Like Tyrosine Kinase 3 (FLT3)-ITD lesions are more sensitive to DOT1L inhibition
Summary
MLL1-rearrangements (MLL-r) account for ~10% of all leukemia cases and are especially prominent in infants (70-80%) and, lacking an effective standard of care, bear a very poor prognosis. A growing body of evidence suggests that MLL-rearrangements rely on additional mutations to cause leukemia. Translocations of MLL1 fuse its amino terminus to the carboxy-terminus of a growing list of over 130 different fusion partners. Translocations of MLL1 fuse its amino terminus to the carboxy-terminus of a growing list of over 130 different fusion partners13 These MLL-fusions lack methyltransferase activity, a functional copy of the MLL1 gene is necessary to target and hypermethylate H3K4 at MLL-fusion target genes to induce leukemogenesis.
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