Abstract
MLL fusion–induced leukemia growth is blocked by DNA damage–dependent differentiation.
Major finding: MLL fusion–induced leukemia growth is blocked by DNA damage–dependent differentiation.
Concept: Genome guardians promote leukemogenesis by enforcing an oncogene–induced differentiation blockade.
Impact: Targeting of the DNA repair machinery may induce differentiation in MLL fusion–driven leukemia.
Most acute lymphoblastic leukemias and acute myeloid leukemias in infants are associated with translocations of mixed-lineage leukemia (MLL) histone methyltransferase genes, which are correlated with poor prognosis and response to therapy. Oncogenic fusions involving MLL1, which is necessary for stem cell self-renewal, disrupt its enzymatic activity, suggesting that deregulated myeloid progenitor self-renewal requires another histone methyltransferase. Utilizing a conditional knockout mouse model, Santos and colleagues investigated the role of the tumor suppressor MLL4 in normal hematopoiesis and MLL-fusion–induced leukemia. MLL4 loss resulted in diminished stress-associated self-renewal and reconstitution capacity of hematopoietic stem cells (HSC) and suppressed the growth of MLL–AF9-induced leukemia. This diminution of self-renewal potential and leukemogenesis in the absence of MLL4 was associated with decreased expression of oxidative stress genes, similar to the transcriptomic changes found in cells deficient for FOXO transcription factors, which protect HSCs against reactive oxygen species (ROS) and maintain leukemic-initiating cells. MLL4 deficiency was phenotypically associated with increased endogenous ROS and DNA damage signaling, as well as a shift toward enhanced myeloid differentiation of leukemic blasts. MLL4-mediated protection from oxidative stress and DNA damage via induction of FOXO3-dependent gene expression was required to enforce the oncogene-induced differentiation block and to promote MLL–AF9-induced leukemia. Furthermore, loss of ATM or BRCA1 impaired self-renewal and triggered myeloid differentiation in MLL–AF9-expressing cells, suggesting that genome instability and accumulation of DNA damage induce myeloid maturation. Indeed, generation of DNA double-strand breaks was sufficient to promote cell-cycle exit and myeloid differentiation via activation of p21. In sum, these data demonstrate that MLL4 and activation of DNA damage response proteins support a myeloid differentiation blockade that is essential for MLL fusion–positive leukemogenesis, and suggest that DNA repair pathway inhibitors may represent an effective differentiation therapy in this disease.