Internal tandem duplication of FLT3 deregulates proliferation and differentiation and confers resistance to the FLT3 inhibitor AC220 by Up-regulating RUNX1 expression in hematopoietic cells

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• 作者：Tomohiro Hirade ; Mariko Abe ; Chie Onishi…
• 关键词：FLT3/ITD ; AML ; RUNX1 ; AC220
• 刊名：International Journal of Hematology
• 出版年：2016
• 出版时间：January 2016
• 年：2016
• 卷：103
• 期：1
• 页码：95-106
• 全文大小：772 KB
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• 作者单位：Tomohiro Hirade (1)
  Mariko Abe (1)
  Chie Onishi (2)
  Takeshi Taketani (1) (3)
  Seiji Yamaguchi (1)
  Seiji Fukuda (1)
  
  1. Department of Pediatrics, Shimane University School of Medicine, 89-1 Enya-cho, Izumo, Shimane, 693-8501, Japan
  2. Department of Oncology/Hematology, Shimane University School of Medicine, Izumo, Japan
  3. Division of Blood Transfusion, Shimane University School of Medicine, Izumo, Japan
  
• 刊物主题：Hematology; Oncology;
• 出版者：Springer Japan
• ISSN：1865-3774

文摘

Internal tandem duplication in the FLT3 gene (FLT3/ITD), which is found in patients with acute myeloid leukemia (AML), causes resistance to FLT3 inhibitors. We found that RUNX1, a transcription factor that regulates normal hematopoiesis, is up-regulated in patients with FLT3/ITD+ AML. While RUNX1 can function as a tumor suppressor, recent data have shown that RUNX1 is required for AML cell survival. In the present study, we investigated the functional role of RUNX1 in FLT3/ITD signaling. FLT3/ITD induced growth factor-independent proliferation and impaired G-CSF mediated myeloid differentiation in 32D hematopoietic cells, coincident with up-regulation of RUNX1 expression. Silencing of RUNX1 expression significantly decreased proliferation and secondary colony formation, and partially abrogated the impaired myeloid differentiation of FLT3/ITD+ 32D cells. Although the number of FLT3/ITD+ 32D cells declined after incubation with the FLT3/ITD inhibitor AC220, the cells became refractory to AC220, concomitant with up-regulation of RUNX1. Silencing of RUNX1 abrogated the emergence and proliferation of AC220-resistant FLT3/ITD+ 32D cells in the presence of AC220. Our data indicate that FLT3/ITD deregulates cell proliferation and differentiation and confers resistance to AC220 by up-regulating RUNX1 expression. These findings suggest an oncogenic role for RUNX1 in FLT3/ITD+ cells and that inhibition of RUNX1 function represents a potential therapeutic strategy in patients with refractory FLT3/ITD+ AML.