New Insights into Epigenetic Regulators of Hematopoietic Stem Cells.

[摘要] Hematopoietic homeostasis relies on the ability of hematopoietic stem cells (HSCs) to maintain both self-renewal potential and multipotency. Disruptions in this balance can lead to abnormal hematopoietic stem and progenitor cell function, and ultimately to hematopoietic failure or hematological malignancies. My studies examined how two epigenetic modifiers, Ash1l and Dot1l, regulate the function of normal hematopoietic stem cells.Absent, small or homeotic discs 1-like (Ash1l) encodes an understudied epigenetic modifier and member of the Trithorax group that has in vitro H3K36 histone methyltransferase (HMT) activity. We discovered that Ash1l is required to establish quiescence and maintain self-renewal potential in adult HSCs. Adult Ash1l-deficient mice had severely reduced phenotypic and functional HSCs, while downstream progenitors proliferated rapidly and maintained steady-state homeostasis. Dual inactivation of Ash1l and the other Trithorax group member, Mixed Lineage Leukemia 1 (Mll1), resulted in hematopoietic failure. Interestingly, genetic inactivation of the histone methyltransferase (HMT) domain of Ash1l did not alter the phenotype or function of HSCs. These results indicate that Ash1l cooperates with Mll1 to regulate hematopoiesis, but operates through mechanisms independent of its intrinsic HMT activity.Disruptor of telomeric silencing 1-like (DOT1L) encodes the only known mammalian H3K79 methyltransferase. DOT1L is required for the maintenance of multiple MLL-driven leukemias and has become an attractive therapeutic target. However, the importance of DOT1L in normal hematopoiesis remains poorly understood. Genetic inactivation of Dot1l resulted in a rapid depletion of HSCs and progenitors and pharmacological inhibition of its methyltransferase activity decreased proliferation and impaired differentiation capacity of progenitors. Genetic disruption of the Dot1l catalytic site indicated that HSCs absolutely require Dotl1’s enzymatic activity to sustain in vivo self-renewal potential. In contrast to Ash1l, Dot1l requires intrinsic enzymatic activity to maintain hematopoiesis.Overall, my studies provide new biological information about the regulation of hematopoiesis by Ash1l and Dot1l, highlighting distinct HMT-independent and HMT-dependent functions. Targeting the HMT activity of ASH1L may be a viable therapeutic strategy since it is dispensable for normal hematopoiesis, whereas targeting DOT1L’s enzymatic activity may harm normal HSCs These studies provide important preclinical information to inform therapeutic strategies to target ASH1L and DOT1L in hematological malignancies.

[发布机构] University of Michigan

[效力级别] epigenetics

[关键词] hematopoietic stem cells;epigenetics;leukemia;histone methyltransferase;Molecular;Cellular and Developmental Biology;Health Sciences;Cellular and Molecular Biology