Hes1 upregulation contributes to the development of FIP1L1-PDGRA-positive leukemia in blast crisis.
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.
Division of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Tomoyuki
T
Uchida
Division of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Jiro
J
Kitaura
Division of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Fumio
F
Nakahara
Division of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Katsuhiro
K
Togami
Division of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Daichi
D
Inoue
Division of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Akie
A
Maehara
Division of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Koutarou
K
Nishimura
Division of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Kimihito C
KC
Kawabata
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.
Noriko
N
Doki
Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan.
Kazuhiko
K
Kakihana
Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan.
Kosuke
K
Yoshioka
Division of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Kumi
K
Izawa
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.
Toshihiko
T
Oki
Heamatology, Department of Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.
Akiko
A
Sada
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.
Yuka
Y
Harada
Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan.
Kazuteru
K
Ohashi
Heamatology, Department of Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.
Yoshio
Y
Katayama
Heamatology, Department of Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.
Toshimitsu
T
Matsui
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.
Hironori
H
Harada
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.
Toshio
T
Kitamura
D019943:Amino Acid Substitution; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis* / Q000235:genetics; D001549:Benzamides / Q000494:pharmacology; D001752:Blast Crisis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D018398:Homeodomain Proteins / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D000068877:Imatinib Mesylate; D007377:Interleukin-3 / Q000096:biosynthesis / Q000235:genetics; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000401:mortality* / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D020125:Mutation, Missense; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011743:Pyrimidines / Q000494:pharmacology; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics / Q000378:metabolism*; D000072056:Transcription Factor HES-1; D039221:mRNA Cleavage and Polyadenylation Factors / Q000235:genetics / Q000378:metabolism*
D000970:Antineoplastic Agents; D051792:Basic Helix-Loop-Helix Proteins; D001549:Benzamides; D018398:Homeodomain Proteins; D000068877:Imatinib Mesylate; D007377:Interleukin-3; D015514:Oncogene Proteins, Fusion; D010879:Piperazines; D011743:Pyrimidines; D020796:Receptor, Platelet-Derived Growth Factor alpha; D000072056:Transcription Factor HES-1; D039221:mRNA Cleavage and Polyadenylation Factors; C489734:Hes1 protein, mouse; C508596:IL3 protein, human; C078493:HES1 protein, human; C479819:FIP1L1-PDGFRA fusion protein, human