Aberrant Megakaryopoiesis in the MPNs
John Crispino
PhDSt. Jude Children's Research Hospital
Project Term: February 1, 2023 - January 31, 2024
A key feature of the MPNs is aberrant megakaryopoiesis, including increased numbers of platelet-producing megakaryocytes in essential thrombocythemia and atypical megakaryocytes that drive fibrosis in myelofibrosis (MF). Recent studies have found that increased activity of the chromosome 21 kinase DYRK1A, which is a feature of the MPNs, enhances megakaryocyte growth while its loss suppresses their expansion. This effect appears to be mediated, at least in part, by DYRK1A’s control of NFAT2 phosphorylation and subcellular localization. The goals of this research are to determine whether DYRK1A is a therapeutic target in chronic phase MPNs and to define the contributions of NFAT2 phosphorylation to the disease.
A defining feature of myelofibrosis (MF) is the accumulation of atypical megakaryocytes, the cells that give rise to platelets. Megakaryocytes contribute to bone marrow fibrosis and other features of the disease by releasing factors that remodel the bone marrow and negatively affect the growth of healthy blood cells. In this project, Drs. Crispino and Tefferi are collaborating to better understand the factors that cause the abnormal development of megakaryocytes in MF. They recently discovered that a gene named DYRK1A enhances megakaryocyte growth while its loss suppresses their expansion. They further found that a protein named NFAT2, which regulates the growth of megakaryocytes, is modified by DYRK1A, and they predict that this change directly promotes aberrant maturation. Their aims are to determine whether DYRK1A is a therapeutic target in chronic phase MPNs and to investigate the contribution of NFAT2 phosphorylation to the disease. Their overarching goal is to leverage these new insights into the development of agents that target aberrant megakaryocytes in MF.