Research Summary

Deciphering the role of Epigenetic mechanism in normal and malignant Hematopoiesis

Hematopoiesis 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.

Figure Legend: Figure 1: NSD1 and NSD3 rearrangement in leukemia Schematic representation of the domain architecture of the normal form of NSD1/NSD3 and the rearranged NSD mutants (Nup98-NSD1/Nup98-NSD3) associated with acute myeloid leukemia (AML) Structural domains are represented by colored symbols. Figure 2: Molecular basis for oncogenicity of NSD fusion proteins Schematic represent the multistep mechanism by which the NSD mutants possibly induces leukemogenesis. The oncogenic potential of NSD mutants’ is generated through a combination of defects in their: target gene binding property; epigenetic/enzymatic properties; and cofactor-binding properties, which are currently not known (missing links marked by?). Identification of these missing links will not only help us in better understanding mechanism of NSD mediated leukemogenesis but also help us in designing more efficient therapy.