ArticleInternational journal of hematology2016
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.
Article in International journal of hematology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed, 14 citations in OpenAlex.
- Targeting transcription factors in cancer - from undruggable to reality.Nature reviews. Cancer · 2019Review
- Quizartinib (AC220): a promising option for acute myeloid leukemia.Drug design, development and therapy · 2019Review
- Risk-stratified therapy for children with FLT3-ITD-positive acute myeloid leukemia: results from the JPLSG AML-05 study.International journal of hematology · 2018Article
- Computer simulations of the signalling network in FLT3BMC bioinformatics · 2018Article
- Article
- FLT3-ITD and its current role in acute myeloid leukaemia.Medical oncology (Northwood, London, England) · 2017Review
- RUNX1 cooperates with FLT3-ITD to induce leukemia.The Journal of experimental medicine · 2017Article
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
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.
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