LAUSR

The property of self-renewal sustains the hematopoietic stem cell (HSC) pool for the lifetime of an organism. While tremendous progress has been made into understanding specific genes and pathways that regulate HSC self-renewal, the molecular mechanisms by which self-renewal is repressed in downstream hematopoietic progenitors is largely unknown. Understanding the mechanisms that restrict self-renewal potential in hematopoietic progenitors may allow augmentation of limited sources of HSCs to improve bone marrow transplantation, or enhance self-renewal potential of progenitor cells in diseases associated with HSC depletion such as aplastic anemia. Polycomb repressive complexes are epigenetic regulators that control multiple aspects of stem cell fate. PRC2 is responsible for the establishment of repressive chromatin mark H3K27me3. While the importance of core PRC2 components in hematopoiesis is established, the function of PRC2 co-factors remains less defined. We recently identified a crucial role for the PRC2 co-factor JARID2 in normal and malignant hematopoiesis. We show that JARID2 is required for epigenetic repression of self-renewal genes in multipotent progenitors (MPPs). Loss of JARID2 leads to acquisition of self-renewal in MPPs, associated with de-repression of self-renewal genes.  In malignant hematopoiesis, deletion of JARID2 lead to accelerated development of MPN or transformation to sAML, depending on the genetic and development context. Our data demonstrate that Jarid2 restricts self-renewal capacity in multipotent progenitors and is a tumor suppressor in chronic myeloid neoplasms. Ongoing studies aim to define how JARID2 expression is regulated in normal development and hematopoietic transformation, how JARID2/PRC2 target specificity is achieved in hematopoietic progenitor cells, and if JARID2 has non-canonical (PRC2-indpendent) functions in hematopoiesis.