Novel mechanisms for STAT5 activation in myeloid neoplasms and acute myeloid leukemia

Myeloproliferative neoplasms (MPNs) include polycythemia vera, essential thrombocythemia and myelofibrosis. The common feature of these disorders is persistent activation of the JAK-STAT pathway, which is mainly induced by mutations in JAK2, MPL and CALR. This thesis addresses the role of STAT5 in both development of CALR-related MPNs and the evolution to secondary acute myeloid leukemia (sAML). Firstly, we show that STAT5 is activated by CALR mutants specifically via MPL and JAK2. This activation occurs in the secretory pathway and on the cell surface. We show that the latter is crucial for transformation. CALR mutants act as rogue chaperones and rescue cell surface localization of MPLs defective in traffic. Secondly, we demonstrate that the release of STAT5 activity from the inhibitory effect of p53 is key for the evolution of MPNs to sAML. STAT5 release requires the loss of both p53 alleles, and it does not require the abolishment of p53 transcriptional activity.