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

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.

• Authors: 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
• Journal: Experimental hematology (Exp Hematol) Vol. 42 Issue 5 Pg. 369-379.e3 (May 2014) ISSN: 1873-2399 [Electronic] Netherlands
• PMID: 24486648 (Publication Type: Clinical Trial, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.

Chemical References

• 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

Topics

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