2. Academic Validation
  3. Hes1 upregulation contributes to the development of FIP1L1-PDGRA-positive leukemia in blast crisis

Hes1 upregulation contributes to the development of FIP1L1-PDGRA-positive leukemia in blast crisis

  • Exp Hematol. 2014 May;42(5):369-379.e3. doi: 10.1016/j.exphem.2014.01.009.
Tomoyuki Uchida 1,  Jiro Kitaura 1,  Fumio Nakahara 1,  Katsuhiro Togami 1,  Daichi Inoue 1,  Akie Maehara 1,  Koutarou Nishimura 1,  Kimihito C Kawabata 1,  Noriko Doki 2,  Kazuhiko Kakihana 3,  Kosuke Yoshioka 3,  Kumi Izawa 1,  Toshihiko Oki 4,  Akiko Sada 5,  Yuka Harada 6,  Kazuteru Ohashi 3,  Yoshio Katayama 5,  Toshimitsu Matsui 5,  Hironori Harada 7,  Toshio Kitamura 8
Affiliations

Affiliations

  • 1 Division of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
  • 2 Division of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan; Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan.
  • 3 Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan.
  • 4 Division of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan; Division of Stem Cell Signaling, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
  • 5 Heamatology, Department of Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.
  • 6 Department of Hematology, Juntendo University School of Medicine, Tokyo, Japan; Division of Radiation Information Registry, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.
  • 7 Department of Hematology, Juntendo University School of Medicine, Tokyo, Japan; Department of Hematology and Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.
  • 8 Division of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan; Division of Stem Cell Signaling, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan. Electronic address: kitamura@ims.u-tokyo.ac.jp.
PMID: 24486648 DOI: 10.1016/j.exphem.2014.01.009
Abstract

We have previously shown that elevated expression of Hairy enhancer of split 1 (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 in only a few cases of 65 samples with different types of myeloid neoplasms. Interestingly, elevated expression of Hes1 was found in two of five samples of Fip1-like1 platelet-derived growth factor receptor-α (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 models, mice transplanted with bone marrow 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, interleukin-3-dependent cells. Imatinib inhibited the growth of common myeloid progenitors 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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