Myeloproliferative Neoplasms (MPNs) are chronic hematologic disorders that are associated with significant morbidity and mortality and have the potential to progress to myelofibrosis and a blast phase. These diseases are characterized by a series of driver mutations that originate at the hematopoietic stem cell (HSC) level, however, the mechanisms driving disease progression are currently unclear. Current therapeutics for MPNs largely do not alter the disease course and it is therefore imperative to decipher the mechanisms underlying progression in order to identify new, more effective therapeutic agents. This proposal focuses on elucidating the role of Phosphatase Mg2+/Mn2+ Dependent 1D (PPM1D) in MPNs and evaluating it as a potential target to prevent MPN disease progression. PPM1D is involved in the maintenance and differentiation of HSCs and has recently been found to be mutated and/or overexpressed in a subset of MPN patients. Preliminary data shows that PPM1D mutation/overexpression leads to increased fitness of the JAK2 mutated MPN clone and that PPM1D inhibition depletes MPN HSCs. To further discern the consequences of dysregulated PPM1D in MPNs we will complete the following aims utilizing a multipronged approach involving primary MPN samples, human induced pluripotent stem cell (iPSC) lines and murine models: (1) Delineate the effects of PPM1D dysregulation on molecular signaling in JAK2V617F+ human hematopoietic cells, (2) Assess the in vivo consequences of PPM1D overexpression on MPN disease phenotype, (3) Identify therapeutic vulnerabilities of MPN cells with dysregulated PPM1D function. Experiments will employ a variety of techniques including biochemical assays, murine transplant models, primary hematopoietic cell colony assays, RNA sequencing and genotyping of transcriptomes. This proposal will also evaluate a novel strategy to target PPM1D in MPNs. Dr. Bridget Marcellino, an assistant professor at the Icahn School of Medicine at Mount Sinai, will be completing these studies under the mentorship of Dr. Ronald Hoffman, a scientific leader in the field of MPNs. She will have 75% of protected research time and will be provided the necessary resources to complete these studies. As an institution Mount Sinai is ideal for fostering the development of physician-scientists with academic seminars and state of the art facilities and resources. Bridget will also have an advisory committee consisting of Dr. Eirini Papapetrou at Mount Sinai, Dr. Ross Levine at Memorial Sloan Kettering Cancer Center, Dr. Dan Avi Landau at Weill Cornell Medical College and biostatisticians, Dr. Amylou Dueck and Heidi Kosiorek at Mayo Clinic. The career development plan outlined here will allow Dr. Marcellino to gain scientific expertise as well as increase her skills in manuscript and grant preparation. This proposal will facilitate Dr. Marcellino to achieve both her short term goal of publishing her findings and her long term goals of developing as a physician-...