Myeloproliferative Neoplasms (MPNs) are clonal diseases of the hematopoietic stem cells (HSC) that lead to excessive myeloid blood cell formation. They start when a HSC acquires either the activating JAK2 V617F mutation, or mutations in thrombopoietin receptor (TpoR/MPL), or frame-shift mutations in the chaperone calreticulin (CALR). After contributing to the identifying JAK2 V617F and TpoR W515 mutations, we defined the structural bases of their pathologic (cytokine-independent) activation. This involves a specific pseudokinase-to-kinase domain circuit for JAK2 V617F and a helix to coil conformational change in the TpoR cytosolic domain for the TpoR W515 mutants. More recently, we showed that frame-shift mutants of CALR acquire the ability to bind and activate TpoR in the secretory pathway and at the cell surface, also leading to JAK2-STAT activation in the megakaryocytic lineage. We use structure-function analysis of driver mutants for identifying JAK2/TpoR and CALR mutant specific inhibitors.

A fraction of MPN patients evolve to severe secondary acute myeloid leukemia (sAML), which has a very poor prognosis. In contrast to de novo AML, p53 mutants are detected in 25% of sAML, while another 20-% of sAML harbor amplification of MDM4 inhibitor of p53. We identified a cross-talk between persistently activated STAT5 and p53 mutants during progression of MPNs to secondary AML. We found that all p53 mutants described in sAML, irrespective of their own transcriptional activity, share the ability to unleash STAT5, which appears crucial for leukemia progression. Chromatin effects of unleashed STAT5 are discussed with respect of self-renewal and differentiation during progression of MPNs to sAML.