INHIBITION OF LSD1 AS A CANDIDATE THERAPEUTIC TARGET IN MYELOPROLIFERATIVE NEOPLASMS

Abstract

An abnormal expansion of megakaryocytes in primary myelofibrosis and essential thrombocythaemia is central to the pathogenesis of these myeloproliferative neoplasms. Despite the introduction of JAK2 inhibitors such as ruxolitinib, there is an unmet clinical need for new treatments of these disorders, particularly in myelofibrosis where survival times from diagnosis remain substantially reduced. At low nanomolar concentrations, a tranylcypromine-derivative inhibitor of lysine-specific demethylase 1 (LSD1) induces a dose-dependent blockade of megakaryocyte expansion and differentiation of primary CD34+ stem and progenitor cells from patients with myelofibrosis. Similar activity was observed in vivo using MPLW515L- and CALRdel52-mutated murine models of pathologic thrombocytosis, where there was reduction of both pathologically high platelet counts and megakaryocyte numbers. These effects were not observed upon equivalent LSD1 inhibitor treatment of normal mice, indicating the presence of a therapeutic window. Bioinformatics analyses demonstrated significant down-regulation in MPLW515L-mutant megakaryocytes of genes associated with megakaryocytic differentiation and pro-platelet formation following LSD1 inhibition. Furthermore, there was significant down-regulation in drug-treated primary patient cells of genes encoding growth factors that promote the bone marrow fibrosis characteristic of myelofibrosis. Expression of a GFI1B-LSD1 fusion in primary CD34+ stem and progenitor cells from patients with myelofibrosis rescued LSD1 inhibitor-induced blockade of megakaryocyte differentiation, suggesting a mechanism of action that is dependent on physical dissociation of LSD1 from GFI1B. Together, these data provide pre-clinical support for evaluation of LSD1 inhibition as a therapeutic strategy in myeloproliferative neoplasms.

Date of Award	31 Dec 2017
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Georges Lacaud (Supervisor) & Tim Somervaille (Supervisor)