The Cell Cycle Regulator CDC25A Is a Target for JAK2^V617F Oncogene

Abstract 1385

The JAK2^V617F mutation is present in the majority of polycythemia vera (PV) patients and half of those with essential thrombocythemia and primary myelofibrosis. JAK2^V617F is a gain-of-function mutation resulting in constitutive JAK2 signalling involved in the pathogenesis of these diseases. JAK2^V617F has been shown to promote S phase entry. Here, we demonstrate that the CDC25A phosphatase, a key regulator of the G1/S cell cycle transition, is constitutively over-expressed in JAK2^V617F -positive cell lines, JAK2-mutated patient CD36+ progenitors and in vitro differentiated proerythroblasts. Accordingly, CDC25A is also overexpressed in bone marrow and spleen of Jak2^V617F knock-in mice compared to wild-type (WT) littermates. Using murine FDC-P1-EPOR and human HEL and SET-2 cell lines, we found that JAK2^V617F-induced CDC25A up-regulation was not caused by increased transcription or CDC25A stability or the involvement of its known upstream regulators AKT and MAPK. Instead, our results suggest that CDC25A is originaly regulated at the translational level through the implication of the transcription factor STAT5 and the translational initiation factor eIF2α. CDC25A inhibition reduces the clonogenic and proliferative potential of JAK2^V617F-expressing erythroid progenitors, while moderately affecting normal erythroid differentiation. These results suggest that CDC25A deregulation may be involved in hematopoietic cells expansion in JAK2^V617F patients, making of this protein an attracting potential therapeutic target.