Exploring strategies to target JAK2-mutant hematopoietic stem cells in myeloproliferative neoplasms

Myeloproliferative Neoplasms (MPNs) are a group of clonal diseases of the hematopoietic stem cell (HSC), in which a gain-of-function mutation in JAK2, CALR or MPL hyperactivates the JAK-STAT signaling pathway, leading to an excess production of erythroid, megakaryocytic and myeloid cells. Because no curative therapies are available, there is a medical need for novel therapeutic strategies that could counteract the hyperproliferation and selectively eliminate the reservoir of mutated HSCs, which is responsible for the maintenance of the MPN clone. Here, I examined two approaches that could open new therapeutic opportunities for patients
with MPN caused by the JAK2-V617F mutation, and I established an experimental system to study the clonal dynamics of JAK2-mutant HSCs in a mouse model of MPN.
In the first part of this thesis I show that targeting the increased metabolic demands of MPN cells by blocking the usage of glutamine (Gln) with the glutaminase inhibitor CB-839 improves most of the clinical manifestat