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

Tomoyuki Uchida; Jiro Kitaura; Fumio Nakahara; Katsuhiro Togami; Daichi Inoue; Akie Maehara; Koutarou Nishimura; Kimihito C Kawabata; Noriko Doki; Kazuhiko Kakihana; Kosuke Yoshioka; Kumi Izawa; Toshihiko Oki; Akiko Sada; Yuka Harada; Kazuteru Ohashi; Yoshio Katayama; Toshimitsu Matsui; Hironori Harada; Toshio Kitamura

doi:10.1016/j.exphem.2014.01.009

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. Epub 2014 Jan 31.

Authors

Tomoyuki Uchida¹, Jiro Kitaura¹, Fumio Nakahara¹, Katsuhiro Togami¹, Daichi Inoue¹, Akie Maehara¹, Koutarou Nishimura¹, Kimihito C Kawabata¹, Noriko Doki², Kazuhiko Kakihana³, Kosuke Yoshioka³, Kumi Izawa¹, Toshihiko Oki⁴, Akiko Sada⁵, Yuka Harada⁶, Kazuteru Ohashi³, Yoshio Katayama⁵, Toshimitsu Matsui⁵, Hironori Harada⁷, Toshio Kitamura⁸

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.

Publication types

Clinical Trial
Multicenter Study
Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Substitution
Animals
Antineoplastic Agents / pharmacology*
Basic Helix-Loop-Helix Transcription Factors / biosynthesis*
Basic Helix-Loop-Helix Transcription Factors / genetics
Benzamides / pharmacology
Blast Crisis / genetics
Blast Crisis / metabolism*
Blast Crisis / pathology
Female
Gene Expression Regulation, Leukemic*
Homeodomain Proteins / biosynthesis*
Homeodomain Proteins / genetics
Humans
Imatinib Mesylate
Interleukin-3 / biosynthesis
Interleukin-3 / genetics
Leukemia, Myeloid, Acute / genetics
Leukemia, Myeloid, Acute / mortality*
Leukemia, Myeloid, Acute / pathology
Male
Mice
Mice, Inbred BALB C
Mutation, Missense
Neoplasms, Experimental / drug therapy
Neoplasms, Experimental / genetics
Neoplasms, Experimental / metabolism*
Neoplasms, Experimental / pathology
Oncogene Proteins, Fusion / genetics
Oncogene Proteins, Fusion / metabolism*
Piperazines / pharmacology
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / drug therapy
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / genetics
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / metabolism
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / pathology
Pyrimidines / pharmacology
Receptor, Platelet-Derived Growth Factor alpha / genetics
Receptor, Platelet-Derived Growth Factor alpha / metabolism*
Transcription Factor HES-1
mRNA Cleavage and Polyadenylation Factors / genetics
mRNA Cleavage and Polyadenylation Factors / metabolism*

Substances

Antineoplastic Agents
Basic Helix-Loop-Helix Transcription Factors
Benzamides
Hes1 protein, mouse
Homeodomain Proteins
IL3 protein, human
Interleukin-3
Oncogene Proteins, Fusion
Piperazines
Pyrimidines
Transcription Factor HES-1
mRNA Cleavage and Polyadenylation Factors
HES1 protein, human
Imatinib Mesylate
FIP1L1-PDGFRA fusion protein, human
Receptor, Platelet-Derived Growth Factor alpha