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.