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Hes1 up-regulation contributes to the development of FIP1L1-PDGFRA-positive leukemia in blast crisis

Authors
  • Uchida, Tomoyuki
  • Kitaura, Jiro
  • Nakahara, Fumio
  • Togami, Katsuhiro
  • Inoue, Daichi
  • Maehara, Akie
  • Nishimura, Koutarou
  • Kawabata, Kimihito C.
  • Doki, Noriko
  • Kakihana, Kazuhiko
  • Yoshioka, Kosuke
  • Izawa, Kumi
  • Oki, Toshihiko
  • Sada, Akiko
  • Harada, Yuka
  • Ohashi, Kazuteru
  • Katayama, Yoshio
  • Matsui, Toshimitsu
  • Harada, Hironori
  • Kitamura, Toshio1, 2, 3, 4, 5, 6, 7, 2, 3, 8, 9, 10, 11, 12, 13, 14, 15, 13, 14
  • 1 Division of Cellular Therapy
  • 2 The Institute of Medical Science
  • 3 The University of Tokyo
  • 4 Hematology Division
  • 5 Tokyo Metropolitan Cancer and Infectious Diseases Center
  • 6 Komagome Hospital
  • 7 Division of Stem Cell Signaling
  • 8 Department of Medicine
  • 9 Kobe University Graduate School of Medicine
  • 10 Department of Hematology
  • 11 Juntendo University School of Medicine
  • 12 Division of Radiation Information Registry
  • 13 Research Institute for Radiation Biology and Medicine
  • 14 Hiroshima University
  • 15 Department of Hematology and Oncology
Type
Published Article
Journal
Experimental Hematology
Publisher
Elsevier
Publication Date
Jan 01, 2014
Accepted Date
Jan 19, 2014
Identifiers
DOI: 10.1016/j.exphem.2014.01.009
Source
Elsevier
Keywords
License
Unknown

Abstract

We have previously shown that elevated expression of Hes1 contributes to blast crisis transition in Bcr-Abl-positive chronic myelogenous leukemia. Here we investigate whether Hes1 is involved in the development of other myeloid neoplasms. Notably, Hes1 expression was elevated only in a few cases out of 65 samples with different types of myeloid neoplasms. Interestingly, elevated expression of Hes1 was found in two out of five samples of Fip1-like1-platelet-derived growth factor receptor alpha (FIP1L1-PDGFA)-positive myeloid neoplasms associated with eosinophilia. Whereas FIP1L1-PDGFRα alone induced acute T-cell leukemia or myeloproliferative neoplasms in mouse bone marrow transplantation (BMT) models, mice transplanted with BM cells expressing both Hes1 and FIP1L1-PDGFRα developed acute leukemia characterized by an expansion of myeloid blasts and leukemic cells without eosinophilic granules. FIP1L1-PDGFRα conferred cytokine-independent growth to Hes1-transduced common myeloid progenitors (CMPs), IL-3-dependent cells. Imatinib inhibited the growth of CMPs expressing Hes1 with FIP1L1-PDGFRα, but not with imatinib-resistant FIP1L1-PDGFRα mutants harboring T674I or D842V. In contrast, ponatinib efficiently eradicated leukemic cells expressing Hes1 and the imatinib-resistant FLP1L1-PDGFRΑ mutant in vitro and in vivo. Thus, we have established mouse models of FIP1L1-PDGFRA-positive leukemia in myeloid blast crisis, which will help elucidate the pathogenesis of the disease and develop a new treatment for it.

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