Role of aberrant cytokine signaling in myeloproliferative disorders

Sloan-Kettering Inst Can Research, New York NY

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Abstract

? DESCRIPTION (provided by applicant): Candidate My ultimate career goal is to become an independent laboratory investigator, with a specific focus in hematologic translational research. My goal is to become the leader of a research program that elucidates the molecular mechanisms of inflammation in hematologic malignancies and that translates basic research findings into new therapies. To achieve my goal, Dr. Levine and I have developed a career development plan with four key elements: 1) To expand and strengthen my experimental and data analysis skills. 2) To enhance my leadership and mentoring skills, 3) To receive advice on my research progress from Dr. Levine and my advisory committee in order to hone my critical thinking and scientific reasoning skills, and 4) To transition from the mentored phase to an independent, tenure-track position during the R00 period. I plan to address these key elements by attending (internal and external) meetings, interactive workshops and didactic sessions. In addition, my collaborators Drs. Fan, Bradner, and Butler are committed to support this project and my career development by providing reagents and expertise. Throughout the entire grant period, I will receive support and guidance from my mentor Dr. Levine and my advisory committee members Drs. Aifantis, Armstrong, and Lowe. During the R00 phase of the award, I will continue to build successful collaborations with experts in the fields of hematology and inflammation. I will focus on the investigation of molecular mechanisms underlying chronic inflammation in MPD and to translate these finding into potential new therapies. Importantly, establishing a strong research line during the duration of this award will allow me to secure future funding of my own laboratory. Environment The proposed study will be conduced at Memorial Sloan Kettering Cancer Center (MSKCC), acknowledged for its exceptional patient care, state-of-the-art facilities, innovative research and outstanding educational programs. As a member of the Levine laboratory, we are part of the Human Oncology and Pathogenesis Program that brings together scientists with an interest in mechanism-based laboratory and translational research. Under the leadership of Dr. Charles Sawyers, HOPP creates a highly collaborative environment that will greatly facilitate my translational research efforts. In additin, I will receive continued guidance and support from my mentor, Dr. Ross Levine who is an outstanding physician-scientist and leader in the MPD field. Research The BCR-ABL-negative myeloproliferative disorders (MPD), primary myelofibrosis (PMF) and post PV/ET myelofibrosis (MF) are associated with significant morbidity and reduced mortality, progressive bone marrow fibrosis and resultant bone marrow failure. PMF patients suffer progressive anemia, remodeling of the bone marrow, splenomegaly, systemic symptoms, and progression to acute leukemia. MPD patients are characterized by systemic inflammation mediated by elevated circulating cytokines, which are presumed to contribute to bone marrow fibrosis, constitutional symptoms, disease pathogenesis and leukemic progression. MPD patients treated with JAK inhibitors experience a significant improvement in constitutional symptoms, which correlates with a marked reduction in plasma cytokine levels. However, the mediators of aberrant cytokine production, the specific populations responsible for aberrant cytokine signaling, and the mechanisms by which JAK inhibitors reverse inflammation have not been investigated in preclinical or clinical contexts. We recently demonstrated that JAK-STAT activation in non-mutant cells contributes to MPD pathogenesis and that JAK kinase inhibition in both mutant and non-mutant cells is required to improve symptoms and reduce disease severity. Our preliminary results suggest that STAT3/NFkB-regulated transcriptional mechanisms drive cytokine signaling in MPD, and that JAK1 signaling is required for MPD pathogenesis and progression. We propose to dissect the mechanisms that mediate aberrant inflammatory signaling in MPD. In Aim1, we will map out cytokine networks in clonally derived hematopoietic cells, in stromal cells, and in non-clonal hematopoietic cells. Aim2 is designed to analyze the mechanisms that govern cytokine signaling in MPD using in vivo models. In Aim3, we will elucidate the mechanisms via which targeted therapies can perturb cytokine networks and impact MPD in vivo. Our studies will include detailed mapping of cytokine production in bulk populations and on a single cell level, genetic studies of pathways mediating cytokine production, mechanistic studies to dissect the mode of action of epigenetic therapies on cytokine expression, and preclinical therapeutic studies aimed to reduce the inflammatory state and to inform future clinical trials. These studies will be initiated during the mentored phase, and will continue into the independent stage of the award, during which we will continue our mechanistic studies and work to identify compounds that would specifically interfere with the host immune response and cytokine expression in MPD models and patient samples.