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Inhibition of BCL2A1 by STAT5 inactivation overcomes resistance to targeted therapies of FLT3-ITD/D835 mutant AML
Tyrosine kinase inhibitors (TKIs) are established drugs in the therapy of FLT3-ITD mutated acute myeloid leukemia (AML). However, acquired mutations, such as D835 in the tyrosine kinase domain (FLT3-ITD/D835), can induce resistance to TKIs. A cap analysis gene expression (CAGE) technology revealed t...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Neoplasia Press
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8818561/ https://www.ncbi.nlm.nih.gov/pubmed/35114569 http://dx.doi.org/10.1016/j.tranon.2022.101354 |
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author | Yamatani, Kotoko Ai, Tomohiko Saito, Kaori Suzuki, Koya Hori, Atsushi Kinjo, Sonoko Ikeo, Kazuho Ruvolo, Vivian Zhang, Weiguo Mak, Po Yee Kaczkowski, Bogumil Harada, Hironori Katayama, Kazuhiro Sugimoto, Yoshikazu Myslinski, Jered Hato, Takashi Miida, Takashi Konopleva, Marina Hayashizaki, Yoshihide Carter, Bing Z. Tabe, Yoko Andreeff, Michael |
author_facet | Yamatani, Kotoko Ai, Tomohiko Saito, Kaori Suzuki, Koya Hori, Atsushi Kinjo, Sonoko Ikeo, Kazuho Ruvolo, Vivian Zhang, Weiguo Mak, Po Yee Kaczkowski, Bogumil Harada, Hironori Katayama, Kazuhiro Sugimoto, Yoshikazu Myslinski, Jered Hato, Takashi Miida, Takashi Konopleva, Marina Hayashizaki, Yoshihide Carter, Bing Z. Tabe, Yoko Andreeff, Michael |
author_sort | Yamatani, Kotoko |
collection | PubMed |
description | Tyrosine kinase inhibitors (TKIs) are established drugs in the therapy of FLT3-ITD mutated acute myeloid leukemia (AML). However, acquired mutations, such as D835 in the tyrosine kinase domain (FLT3-ITD/D835), can induce resistance to TKIs. A cap analysis gene expression (CAGE) technology revealed that the gene expression of BCL2A1 transcription start sites was increased in primary AML cells bearing FLT3-ITD/D835 compared to FLT3-ITD. Overexpression of BCL2A1 attenuated the sensitivity to quizartinib, a type II TKI, and venetoclax, a selective BCL2 inhibitor, in AML cell lines. However, a type I TKI, gilteritinib, inhibited the expression of BCL2A1 through inactivation of STAT5 and alleviated TKI resistance of FLT3-ITD/D835. The combination of gilteritinib and venetoclax showed synergistic effects in the FLT3-ITD/D835 positive AML cells. The promoter region of BCL2A1 contains a BRD4 binding site. Thus, the blockade of BRD4 with a BET inhibitor (CPI-0610) downregulated BCL2A1 in FLT3-mutated AML cells and extended profound suppression of FLT3-ITD/D835 mutant cells. Therefore, we propose that BCL2A1 has the potential to be a novel therapeutic target in treating FLT3-ITD/D835 mutated AML. |
format | Online Article Text |
id | pubmed-8818561 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Neoplasia Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-88185612022-02-09 Inhibition of BCL2A1 by STAT5 inactivation overcomes resistance to targeted therapies of FLT3-ITD/D835 mutant AML Yamatani, Kotoko Ai, Tomohiko Saito, Kaori Suzuki, Koya Hori, Atsushi Kinjo, Sonoko Ikeo, Kazuho Ruvolo, Vivian Zhang, Weiguo Mak, Po Yee Kaczkowski, Bogumil Harada, Hironori Katayama, Kazuhiro Sugimoto, Yoshikazu Myslinski, Jered Hato, Takashi Miida, Takashi Konopleva, Marina Hayashizaki, Yoshihide Carter, Bing Z. Tabe, Yoko Andreeff, Michael Transl Oncol Original Research Tyrosine kinase inhibitors (TKIs) are established drugs in the therapy of FLT3-ITD mutated acute myeloid leukemia (AML). However, acquired mutations, such as D835 in the tyrosine kinase domain (FLT3-ITD/D835), can induce resistance to TKIs. A cap analysis gene expression (CAGE) technology revealed that the gene expression of BCL2A1 transcription start sites was increased in primary AML cells bearing FLT3-ITD/D835 compared to FLT3-ITD. Overexpression of BCL2A1 attenuated the sensitivity to quizartinib, a type II TKI, and venetoclax, a selective BCL2 inhibitor, in AML cell lines. However, a type I TKI, gilteritinib, inhibited the expression of BCL2A1 through inactivation of STAT5 and alleviated TKI resistance of FLT3-ITD/D835. The combination of gilteritinib and venetoclax showed synergistic effects in the FLT3-ITD/D835 positive AML cells. The promoter region of BCL2A1 contains a BRD4 binding site. Thus, the blockade of BRD4 with a BET inhibitor (CPI-0610) downregulated BCL2A1 in FLT3-mutated AML cells and extended profound suppression of FLT3-ITD/D835 mutant cells. Therefore, we propose that BCL2A1 has the potential to be a novel therapeutic target in treating FLT3-ITD/D835 mutated AML. Neoplasia Press 2022-02-01 /pmc/articles/PMC8818561/ /pubmed/35114569 http://dx.doi.org/10.1016/j.tranon.2022.101354 Text en © 2022 Published by Elsevier Inc. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Original Research Yamatani, Kotoko Ai, Tomohiko Saito, Kaori Suzuki, Koya Hori, Atsushi Kinjo, Sonoko Ikeo, Kazuho Ruvolo, Vivian Zhang, Weiguo Mak, Po Yee Kaczkowski, Bogumil Harada, Hironori Katayama, Kazuhiro Sugimoto, Yoshikazu Myslinski, Jered Hato, Takashi Miida, Takashi Konopleva, Marina Hayashizaki, Yoshihide Carter, Bing Z. Tabe, Yoko Andreeff, Michael Inhibition of BCL2A1 by STAT5 inactivation overcomes resistance to targeted therapies of FLT3-ITD/D835 mutant AML |
title | Inhibition of BCL2A1 by STAT5 inactivation overcomes resistance to targeted therapies of FLT3-ITD/D835 mutant AML |
title_full | Inhibition of BCL2A1 by STAT5 inactivation overcomes resistance to targeted therapies of FLT3-ITD/D835 mutant AML |
title_fullStr | Inhibition of BCL2A1 by STAT5 inactivation overcomes resistance to targeted therapies of FLT3-ITD/D835 mutant AML |
title_full_unstemmed | Inhibition of BCL2A1 by STAT5 inactivation overcomes resistance to targeted therapies of FLT3-ITD/D835 mutant AML |
title_short | Inhibition of BCL2A1 by STAT5 inactivation overcomes resistance to targeted therapies of FLT3-ITD/D835 mutant AML |
title_sort | inhibition of bcl2a1 by stat5 inactivation overcomes resistance to targeted therapies of flt3-itd/d835 mutant aml |
topic | Original Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8818561/ https://www.ncbi.nlm.nih.gov/pubmed/35114569 http://dx.doi.org/10.1016/j.tranon.2022.101354 |
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