The MPN-RC Structure

Thirteen different institutions are currently participating in the MPN-RC. Each institution has its own unique intellectual environment, clinical and research facilities.

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Discovery Science

Project 1

Molecular Pathogenesis and Therapy of Myeloproliferative Neoplasms

Discovery Science

Project 2

Defining the Role of Megakaryocyte Abnormalties in the Progression of Primary Myelofibrosis

Discovery Science

Project 3

Development of Strategies to Deplete Myelofibrosis Stem Cells

Discovery Science

Project 4

MPN-RC Clinical Consortium

All Projects

Project 1: Molecular Pathogenesis and Therapy of Myeloproliferative Neoplasms

Principal Investigator: Ross Levine, PhD

Dr. Ross Levine will develop strategies that more effectively target JAK-STAT signaling than the currently available JAK1/2 inhibitors which have been approved by the FDA.  He will explore how mutations in a signaling effector (JAK2) and a chromatin modulator (ASXL1) cooperate to dysregulate epigenetic/transcriptional output, alter signaling and promote disease progression.  He will then evaluate how treatment with type II JAK2 inhibitors alone and in combination with epigenetic directed agents, such as an EZH2 inhibitor, are effective at depleting MPN HSCs with a specific focus on ASXL1-mutant, high risk MF.

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Project 2: Defining the Role of Megakaryocyte Abnormalties in the Progression of Primary Myelofibrosis

Principal Investigator: John Crispino (PI), PhD Annarita Migliaccio (co-PI), PhD

Drs. John Crispino and Anna Rita Migliaccio will focus on impact of megakaryocytic hyperplasia, one of the histopathological hallmarks of the MPNs, on MF pathogenesis. They will investigate if bone marrow fibrosis and disease progression is driven by aberrant cytokine secretion by abnormal megakaryocytes that are dysregulated by reduced expression of GATA1. Studying the effects of GATA1 deficiency on megakaryocyte maturation and on cytokine secretion provides an opportunity to identify additional therapeutic targets. In addition, the effects of TGF-β, which is elaborated by MF megakaryocytes, on normal and MF HSCs and HPCs will be assessed. Data generated during the prior funding period have led to a clinical trial of a TGF-β receptor kinase inhibitor, galunisertib, (MPN-RC Clinical Trial 118) in patients with advanced forms of MF.

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Project 3: Development of Strategies to Deplete Myelofibrosis Stem Cells

Principal Investigator: Ronald Hoffman, MD

Dr. Ronald Hoffman will explore whether the dysregulated p53/HDM2/4 pathway can be exploited to deplete MF HSCs. He has shown that HDM2 is up regulated in MF HSCs leading to the down regulation of the transcriptional regulator P53 and resulting in predominance of MF HSCs. He also reported that HDM2 in MF and PV) HSCs can be targeted with the orally available nutlin, RG7388 (idasanutlin), leading to a depletion of MPN HSCs which forms the basis for the MPN-RC 115 and MPN-116 clinical trials in PV and MF patients, respectively (Project 4). He will also examine whether the inflammatory mediators elaborated by MF cells which deplete normal HSCs and promote the predominance of MPN HSCs corrupt tissue specific microenvironments so as to further fuel disease progression. His efforts will focus on the role of attenuation of P53 signaling in MF HSCs, and on the role of the LCN2-IL-8 axis in altering the HSC/microenvironmental interaction to favor MPN HSCs and to allow MPN HSC to colonize the spleen and to promote systemic inflammation and bone marrow fibrosis. These will be tested using novel therapeutic probes in human MPN cells/novel model systems to allow for translation to Project 4 for clinical trials.

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Project 4: MPN-RC Clinical Consortium

Principal Investigator: John Mascarenhas (PI), MD Ruben Mesa (co-PI), MD

“The MPN Clinical Consortium” is the clinical hub of the MPN-RC and is directed by Drs. John Mascarenhas and Ruben Mesa. They will pursue a series of hypothesis testing clinical trials which will each be directed toward depleting or eliminating MPN HSCs and/or inhibiting aberrant inflammatory signaling supporting this malignant HSC population. They will focus on mechanism-based early phase (I/II) clinical trials that emanate from the laboratory projects and which test and credential novel single and combination therapeutic approaches based on biological insights.

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