title: The cell cycle regulator CDC25A is a target for JAK2V617F oncogene.
abstract: The JAK2(V617F) mutation is present in the majority of patients with polycythemia vera and one-half of those with essential thrombocythemia and primary myelofibrosis. JAK2(V617F) is a gain-of-function mutation resulting in constitutive JAK2 signaling 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 overexpressed in JAK2(V617F)-positive cell lines, JAK2-mutated patient CD36(+) progenitors, and in vitro-differentiated proerythroblasts. Accordingly, CDC25A is overexpressed in BM and spleen of Jak2(V617F) knock-in mice compared with wild-type littermates. By using murine FDC-P1-EPOR and human HEL and SET-2 cell lines, we found that JAK2(V617F)-induced CDC25A up-regulation was caused neither by increased CDC25A transcription or stability nor by the involvement of its upstream regulators Akt and MAPK. Instead, our results suggest that CDC25A is regulated at the translational level through STAT5 and the translational initiation factor eIF2α. CDC25A inhibition reduces the clonogenic and proliferative potential of JAK2(V617F)-expressing cell lines and 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 this protein an attracting potential therapeutic target.
authors: INSERM UMR 1037-Cancer Research Center of Toulouse, Université de Toulouse, Centre Hospitalier Universitaire Purpan, Toulouse, France.
authors: Emilie-Fleur
authors: EF
authors: Gautier
authors: Muriel
authors: M
authors: Picard
authors: Camille
authors: C
authors: Laurent
authors: Caroline
authors: C
authors: Marty
authors: Jean-Luc
authors: JL
authors: Villeval
authors: Cécile
authors: C
authors: Demur
authors: François
authors: F
authors: Delhommeau
authors: Elizabeth
authors: E
authors: Hexner
authors: Stéphane
authors: S
authors: Giraudier
authors: Nicolas
authors: N
authors: Bonnevialle
authors: Bernard
authors: B
authors: Ducommun
authors: Christian
authors: C
authors: Récher
authors: Guy
authors: G
authors: Laurent
authors: Stéphane
authors: S
authors: Manenti
authors: Véronique
authors: V
authors: Mansat-De Mas
mesh_terms: D019943:Amino Acid Substitution / Q000502:physiology; D000818:Animals; D002453:Cell Cycle / Q000235:genetics; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000235:genetics; D015973:Gene Expression Regulation, Leukemic / Q000235:genetics; D019337:Hematologic Neoplasms / Q000235:genetics / Q000473:pathology; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D050505:Mutant Proteins / Q000235:genetics; D009857:Oncogenes / Q000235:genetics; D010649:Phenylalanine / Q000235:genetics; D015854:Up-Regulation; D014633:Valine / Q000235:genetics; D020687:cdc25 Phosphatases / Q000235:genetics* / Q000378:metabolism
chemical_list: D050505:Mutant Proteins; D010649:Phenylalanine; C507924:JAK2 protein, human; D053614:Janus Kinase 2; C517004:CDC25A protein, human; D020687:cdc25 Phosphatases; D014633:Valine