Major finding: Dnmt1 haploinsufficiency impairs LSC self-renewal and delays leukemogenesis.
Mechanism: DNA methylation promotes repression of bivalent chromatin domains.
Impact: Targeting DNMT1 may achieve a favorable therapeutic index in AML.
DNA methylation is a known regulator of both normal hematopoietic and leukemia stem cell function, but it remains unclear whether DNA methyltransferase activity and DNA methylation patterns are sufficiently unique in leukemic stem cells (LSC) to be well-suited for targeted therapy. Using a mouse model of MLL–AF9-induced acute myeloid leukemia (AML), Trowbridge and colleagues showed that DNA methyltransferase 1 (Dnmt1), but not Dnmt3a or Dnmt3b, was highly expressed in LSCs, suggesting that DNMT1 may specifically regulate DNA methylation in these cells. Conditional deletion of Dnmt1 in the MLL–AF9 background completely blocked leukemic transformation, delayed progression of preexisting MLL–AF9-induced leukemias, and impaired the ability of MLL–AF9 LSCs to establish disease in secondary recipients. Dnmt1 haploinsufficiency was also sufficient to significantly delay MLL–AF9-induced leukemic progression, and impairment of DNA methylation by deletion of one Dnmt1 allele or pharmacologic inhibition of DNMT1 activity suppressed LSC survival, self-renewal, and differentiation in vitro without affecting normal hematopoietic stem/progenitor cell survival. Genome-wide expression profiling revealed that Dnmt1 haploinsufficiency led to derepression of a specific subset of genes in MLL–AF9 LSCs, including multiple tumor suppressors, that was associated with a reduction in the bivalent histone H3 lysine-4 and lysine-27 trimethylation that normally demarcates silent genes. Together, these findings suggest a model in which MLL–AF9 LSCs require DNMT1-mediated DNA methylation for epigenetic silencing of genes that inhibit self-renewal and leukemogenesis and indicate that specific targeting of DNMT1 may achieve a favorable therapeutic index in patients with AML.
Trowbridge JJ, Sinha AU, Zhu N, Li M, Armstrong SA, Orkin SH. Haploinsufficiency of Dnmt1 impairs leukemia stem cell function through derepression of bivalent chromatin domains. Genes Dev 2012;26:344–9.
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