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
  • 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: [email protected].
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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