title: Loss of p53 induces leukemic transformation in a murine model of Jak2 V617F-driven polycythemia vera.
abstract: As leukemic transformation of myeloproliferative neoplasms (MPNs) worsens the clinical outcome, reducing the inherent risk of the critical event in MPN cases could be beneficial. Among genetic alterations concerning the transformation, the frequent one is TP53 mutation. Here we show that retroviral overexpression of Jak2 V617F mutant into wild-type p53 murine bone marrow cells induced polycythemia vera (PV) in the recipient mice, whereas Jak2 V617F-transduced p53-null mice developed lethal leukemia after the preceding PV phase. The leukemic mice had severe anemia, hepatosplenomegaly, pulmonary hemorrhage and expansion of dysplastic erythroid progenitors. Primitive leukemia cells (c-kit+Sca1+Lin-(KSL) and CD34-CD16/32-c-kit+Sca1-Lin-(megakaryocyte-erythroid progenitor; MEP)) and erythroid progenitors (CD71+) from Jak2 V617F-transduced p53-null leukemic mice had leukemia-initiating capacity, however, myeloid differentiated populations (Mac-1+) could not recapitulate the disease. Interestingly, recipients transplanted with CD71+cells rapidly developed erythroid leukemia, which was in sharp contrast to leukemic KSL cells to cause lethal leukemia after the polycythemic state. The leukemic CD71+cells were more sensitive to INCB18424, a potent JAK inhibitor, than KSL cells. p53 restoration could ameliorate Jak2 V617F-transduced p53-null erythroleukemia. Taken together, our results show that p53 loss is sufficient for inducing leukemic transformation in Jak2 V617F-positive MPN.
authors.affiliation: Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Tsuruta-Kishino
authors.affiliation: Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.
authors.forename: J
authors.initials: J
authors.lastname: Koya
authors.affiliation: Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Kataoka
authors.affiliation: Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Narukawa
authors.affiliation: Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.|Oncology Research Laboratories, Kyowa Hakko Kirin Co., Machida, Tokyo, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Sumitomo
authors.affiliation: Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Kobayashi
authors.affiliation: Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.|Department of Transfusion Medicine, The University of Tokyo Hospital, Bunkyo-ku, Tokyo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Sato
authors.affiliation: Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.|Department of Cell Therapy and Transplantation, The University of Tokyo Hospital, Bunkyo-ku, Tokyo, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Kurokawa
mesh_terms: D000818:Animals; D017209:Apoptosis; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D005260:Female; D053614:Janus Kinase 2 / Q000235:genetics*; D007942:Leukemia, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics*; D011087:Polycythemia Vera / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
chemical_list: D016159:Tumor Suppressor Protein p53; D053614:Janus Kinase 2