title: Essential role for Stat5a/b in myeloproliferative neoplasms induced by BCR-ABL1 and JAK2(V617F) in mice.
abstract: STAT5 proteins are constitutively activated in malignant cells from many patients with leukemia, including the myeloproliferative neoplasms (MPNs) chronic myeloid leukemia (CML) and polycythemia vera (PV), but whether STAT5 is essential for the pathogenesis of these diseases is not known. In the present study, we used mice with a conditional null mutation in the Stat5a/b gene locus to determine the requirement for STAT5 in MPNs induced by BCR-ABL1 and JAK2(V617F) in retroviral transplantation models of CML and PV. Loss of one Stat5a/b allele resulted in a decrease in BCR-ABL1-induced CML-like MPN and the appearance of B-cell acute lymphoblastic leukemia, whereas complete deletion of Stat5a/b prevented the development of leukemia in primary recipients. However, BCR-ABL1 was expressed and active in Stat5-null leukemic stem cells, and Stat5 deletion did not prevent progression to lymphoid blast crisis or abolish established B-cell acute lymphoblastic leukemia. JAK2(V617F) failed to induce polycythemia in recipients after deletion of Stat5a/b, although the loss of STAT5 did not prevent the development of myelofibrosis. These results demonstrate that STAT5a/b is essential for the induction of CML-like leukemia by BCR-ABL1 and of polycythemia by JAK2(V617F), and validate STAT5a/b and the genes they regulate as targets for therapy in these MPNs.
authors.affiliation: Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA 02111, USA.
authors.forename: Christoph
authors.initials: C
authors.lastname: Walz
authors.forename: Wesam
authors.initials: W
authors.lastname: Ahmed
authors.forename: Katherine
authors.initials: K
authors.lastname: Lazarides
authors.forename: Monica
authors.initials: M
authors.lastname: Betancur
authors.forename: Nihal
authors.initials: N
authors.lastname: Patel
authors.forename: Lothar
authors.initials: L
authors.lastname: Hennighausen
authors.forename: Virginia M
authors.initials: VM
authors.lastname: Zaleskas
authors.forename: Richard A
authors.initials: RA
authors.lastname: Van Etten
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D019046:Bone Marrow Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology; D016313:Genes, abl / Q000235:genetics / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics / Q000502:physiology*; D051379:Mice; D020297:Mice, Congenic; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D020125:Mutation, Missense / Q000502:physiology; D009196:Myeloproliferative Disorders / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D041681:NIH 3T3 Cells; D010649:Phenylalanine / Q000235:genetics; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014633:Valine / Q000235:genetics
chemical_list: D050799:STAT5 Transcription Factor; C494093:Stat5a protein, mouse; C494096:Stat5b protein, mouse; D010649:Phenylalanine; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2; D014633:Valine