Myeloproliferative Neoplasms: From Biology to Targeted Therapeutics

Marinaccio, Christian

doi:https://doi.org/10.21985/n2-rwhc-f667

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Myeloproliferative Neoplasms: From Biology to Targeted Therapeutics

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The BCR-ABL negative Myeloproliferative Neoplasms (MPNs) are clonal hematopoietic stem-cell disorders characterized by abnormal proliferation of differentiated myeloid lineages. MPNs include 3 clinically distinct disorders: Polycythemia Vera (PV), Essential Thrombocythemia (ET) and Primary Myelofibrosis (PMF). 95% of MPNs are characterized by driver mutations in Janus Kinase 2 (JAK2), Thrombopoietin receptor (MPL) and Calreticulin (CALR) which each lead to constitutive activation of the JAK-STAT signaling pathway. PMF is the most aggressive subtype of MPN, characterized by elevated white blood counts, splenomegaly and bone marrow fibrosis. The median survival of these patients in the high-risk category is 16 months, and the two only current FDA approved targeted therapies for PMF are Ruxolitinib and Fedratinib, JAK2 inhibitors that provide therapeutic benefits, but are limited by toxicity and eventual resistance. A striking feature of PMF is the presence of an expanded population of atypical megakaryocytes which are thought to have a major role in the development of the disease. We previously showed that targeting megakaryocytes with the Aurora Kinase A (AURKA) inhibitor Alisertib resulted in reduced disease burden and bone marrow fibrosis in preclinical mouse models of MPN. The first part of this dissertation describes the results of a multi-center Phase I clinical trial that was carried out at Northwestern University in collaboration with Mayo Clinic and Miami University evaluating the safety and preliminary clinical activity of Alisertib in the treatment of PMF. We show that Alisertib has on-target effects on the megakaryocyte lineage, including normalization of bone marrow megakaryocyte morphology and decreased bone marrow fibrosis. Furthermore, MPNs are characterized by progression to an aggressive form of Acute Myeloid Leukemia named Blast-Phase MPN (MPN-BP). MPN patients transform to MPN-BP with rates of 10-20%, 2-5% ad 1-4% in PMF, PV and ET, respectively. MPN-BP has a dismal prognosis with a median survival of only 3-5 months, and the drivers of transformation of MPNs to MPN-BP are largely unknown. In the second part of this dissertation, we describe the involvement of Serine Threonine Kinase 11/Liver Inducible Kinase 1 (STK11/LKB1) in the progression of MPN to MPN-BP. With my collaborators I show that loss of STK11/LKB1 in MPN cells is associated with enhanced self-renewal in-vitro and rapid lethality in a mouse model of MPN. Furthermore, we show that loss of STK11/LKB1 cause increase of mitochondrial reactive oxygen species (mitoROS) that lead to stabilization of hypoxia inducible protein 1a (HIF1a). Finally, we provide evidence of increased HIF1a stabilization and STK11/LKB1 loss in human MPN-BP.

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