Uncovering the mechanism of DYRK1A in lymphopoiesis and acute lymphoblastic leukemia

My lab has shown that the chromosome 21 kinase DYRK1A is necessary for normal lymphocyte development in part through the Cyclin D3-Rb-E2F pathway(1). This mechanism appears to govern the switch between proliferation and quiescence, but the way in which DYRK1A regulates differentiation is unclear. In addition to disruption of normal development, the loss of Dyrk1a also impairs proliferative ability of acute lymphoblastic leukemia (ALL) cells, suggesting that it has a multi-faceted role in lymphocyte biology. My goal is to illustrate a complete mechanism of DYRK1A in developing lymphocytes and to see how this changes upon leukemic transformation. I hypothesize that DYRK1A regulates a number of intracellular pathways that regulate the growth and differentiation of lymphoid cells, and that its dysregulation contributes to ALL.