Research Summary
Deciphering the role of Epigenetic mechanism in normal and malignant HematopoiesisHematopoiesis is a dynamic process that is tightly regulated at the transcriptional level by epigenetic modifications. Growing amount of evidence suggests that alterations in the epigenetic enzymes regulating these modifications are a leading cause in leukemia initiation and progression. The Nuclear Receptor Binding SET Domain (NSD) containing histone methyltransferase family of enzymes has three members NSD1, NSD2/MMSET/WHSC, and NSD3/WHSC1L1. Deregulated expression of NSD histone methyltransferases due to alterations and/or amplification can disrupt normal hematopoiesis and induces leukemogenesis or development of leukemia. NSD1 and NSD3 undergo chromosomal translocation with the nucleoporin gene (NUP98) to form oncogenic fusion proteins NUP98-NSD1 and NUP98-NSD3 that mediates Acute Myeloid Leukemia (AML). The reactivation of specific genes upon expression of NSD mutants in hematopoietic cells leads to oncogenic transformation, such that these cells acquire new properties including increased proliferation, unlimited self renewal and/or inhibited apoptosis and differentiation. However, currently it is unclear how the oncogenic NSD mutants’ work at the molecular level to alter gene expression and most importantly, to which extent their role as epigenetic regulators differs from that of the “normal” NSD proteins. The long term goal of the current research proposal is to elucidate the molecular mechanism by which NSD mutants’ causes leukemogenesis.