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CD52 is a novel target for the treatment of FLT3-ITD-mutated myeloid leukemia

Internal tandem duplication (ITD) of FMS-like tyrosine kinase 3 (FLT3) confers poor prognosis and is found in approximately 25% of cases of acute myeloid leukemia (AML). Although FLT3 inhibitors have shown clinical benefit in patients with AML harboring FLT3-ITD, the therapeutic effect is limited. H...

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Autores principales: Karnan, Sivasundaram, Hanamura, Ichiro, Ota, Akinobu, Takasugi, Souichi, Nakamura, Ayano, Takahashi, Miyuki, Uchino, Kaori, Murakami, Satsuki, Wahiduzzaman, Md, Quang Vu, Lam, Rahman, Md Lutfur, Hasan, Muhammad Nazmul, Hyodo, Toshinori, Konishi, Hiroyuki, Tsuzuki, Shinobu, Yoshikawa, Kazuhiro, Suzuki, Susumu, Ueda, Ryuzo, Ejiri, Masayuki, Hosokawa, Yoshitaka, Takami, Akiyoshi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8149417/
https://www.ncbi.nlm.nih.gov/pubmed/34035227
http://dx.doi.org/10.1038/s41420-021-00446-8
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author Karnan, Sivasundaram
Hanamura, Ichiro
Ota, Akinobu
Takasugi, Souichi
Nakamura, Ayano
Takahashi, Miyuki
Uchino, Kaori
Murakami, Satsuki
Wahiduzzaman, Md
Quang Vu, Lam
Rahman, Md Lutfur
Hasan, Muhammad Nazmul
Hyodo, Toshinori
Konishi, Hiroyuki
Tsuzuki, Shinobu
Yoshikawa, Kazuhiro
Suzuki, Susumu
Ueda, Ryuzo
Ejiri, Masayuki
Hosokawa, Yoshitaka
Takami, Akiyoshi
author_facet Karnan, Sivasundaram
Hanamura, Ichiro
Ota, Akinobu
Takasugi, Souichi
Nakamura, Ayano
Takahashi, Miyuki
Uchino, Kaori
Murakami, Satsuki
Wahiduzzaman, Md
Quang Vu, Lam
Rahman, Md Lutfur
Hasan, Muhammad Nazmul
Hyodo, Toshinori
Konishi, Hiroyuki
Tsuzuki, Shinobu
Yoshikawa, Kazuhiro
Suzuki, Susumu
Ueda, Ryuzo
Ejiri, Masayuki
Hosokawa, Yoshitaka
Takami, Akiyoshi
author_sort Karnan, Sivasundaram
collection PubMed
description Internal tandem duplication (ITD) of FMS-like tyrosine kinase 3 (FLT3) confers poor prognosis and is found in approximately 25% of cases of acute myeloid leukemia (AML). Although FLT3 inhibitors have shown clinical benefit in patients with AML harboring FLT3-ITD, the therapeutic effect is limited. Here, to explore alternative therapeutics, we established a cellular model of monoallelic FLT3(ITD/WT) cells using the CRISPR-Cas9 system in a human myeloid leukemia cell line, K562. cDNA microarray analysis revealed elevated CD52 expression in K562–FLT3(ITD/WT) cells compared to K562–FLT3(WT/WT) cells, an observation that was further confirmed by quantitative real-time-PCR and flow cytometric analyses. The elevated expression of CD52 in K562–FLT3(ITD/WT) cells was decreased in wild-type FLT3 (FLT3-WT) knock-in K562–FLT3(ITD/WT) cells. In K562–FLT3(ITD/WT) cells, a STAT5 inhibitor, pimozide, downregulated CD52 protein expression while an AKT inhibitor, afuresertib, did not affect CD52 expression. Notably, an anti-CD52 antibody, alemtuzumab, induced significant antibody-dependent cell-mediated cytotoxicity (ADCC) in K562-FLT3(ITD/WT) cells compared to K562–FLT3(WT/WT) cells. Furthermore, alemtuzumab significantly suppressed the xenograft tumor growth of K562–FLT3(ITD/WT) cells in severe combined immunodeficiency (SCID) mice. Taken together, our data suggested that genetically modified FLT3-ITD knock-in human myeloid leukemia K562 cells upregulated CD52 expression via activation of STAT5, and alemtuzumab showed an antitumor effect via induction of ADCC in K562–FLT3(ITD/WT) cells. Our findings may allow establishment of a new therapeutic option, alemtuzumab, to treat leukemia with the FLT3-ITD mutation.
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spelling pubmed-81494172021-05-27 CD52 is a novel target for the treatment of FLT3-ITD-mutated myeloid leukemia Karnan, Sivasundaram Hanamura, Ichiro Ota, Akinobu Takasugi, Souichi Nakamura, Ayano Takahashi, Miyuki Uchino, Kaori Murakami, Satsuki Wahiduzzaman, Md Quang Vu, Lam Rahman, Md Lutfur Hasan, Muhammad Nazmul Hyodo, Toshinori Konishi, Hiroyuki Tsuzuki, Shinobu Yoshikawa, Kazuhiro Suzuki, Susumu Ueda, Ryuzo Ejiri, Masayuki Hosokawa, Yoshitaka Takami, Akiyoshi Cell Death Discov Article Internal tandem duplication (ITD) of FMS-like tyrosine kinase 3 (FLT3) confers poor prognosis and is found in approximately 25% of cases of acute myeloid leukemia (AML). Although FLT3 inhibitors have shown clinical benefit in patients with AML harboring FLT3-ITD, the therapeutic effect is limited. Here, to explore alternative therapeutics, we established a cellular model of monoallelic FLT3(ITD/WT) cells using the CRISPR-Cas9 system in a human myeloid leukemia cell line, K562. cDNA microarray analysis revealed elevated CD52 expression in K562–FLT3(ITD/WT) cells compared to K562–FLT3(WT/WT) cells, an observation that was further confirmed by quantitative real-time-PCR and flow cytometric analyses. The elevated expression of CD52 in K562–FLT3(ITD/WT) cells was decreased in wild-type FLT3 (FLT3-WT) knock-in K562–FLT3(ITD/WT) cells. In K562–FLT3(ITD/WT) cells, a STAT5 inhibitor, pimozide, downregulated CD52 protein expression while an AKT inhibitor, afuresertib, did not affect CD52 expression. Notably, an anti-CD52 antibody, alemtuzumab, induced significant antibody-dependent cell-mediated cytotoxicity (ADCC) in K562-FLT3(ITD/WT) cells compared to K562–FLT3(WT/WT) cells. Furthermore, alemtuzumab significantly suppressed the xenograft tumor growth of K562–FLT3(ITD/WT) cells in severe combined immunodeficiency (SCID) mice. Taken together, our data suggested that genetically modified FLT3-ITD knock-in human myeloid leukemia K562 cells upregulated CD52 expression via activation of STAT5, and alemtuzumab showed an antitumor effect via induction of ADCC in K562–FLT3(ITD/WT) cells. Our findings may allow establishment of a new therapeutic option, alemtuzumab, to treat leukemia with the FLT3-ITD mutation. Nature Publishing Group UK 2021-05-25 /pmc/articles/PMC8149417/ /pubmed/34035227 http://dx.doi.org/10.1038/s41420-021-00446-8 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Karnan, Sivasundaram
Hanamura, Ichiro
Ota, Akinobu
Takasugi, Souichi
Nakamura, Ayano
Takahashi, Miyuki
Uchino, Kaori
Murakami, Satsuki
Wahiduzzaman, Md
Quang Vu, Lam
Rahman, Md Lutfur
Hasan, Muhammad Nazmul
Hyodo, Toshinori
Konishi, Hiroyuki
Tsuzuki, Shinobu
Yoshikawa, Kazuhiro
Suzuki, Susumu
Ueda, Ryuzo
Ejiri, Masayuki
Hosokawa, Yoshitaka
Takami, Akiyoshi
CD52 is a novel target for the treatment of FLT3-ITD-mutated myeloid leukemia
title CD52 is a novel target for the treatment of FLT3-ITD-mutated myeloid leukemia
title_full CD52 is a novel target for the treatment of FLT3-ITD-mutated myeloid leukemia
title_fullStr CD52 is a novel target for the treatment of FLT3-ITD-mutated myeloid leukemia
title_full_unstemmed CD52 is a novel target for the treatment of FLT3-ITD-mutated myeloid leukemia
title_short CD52 is a novel target for the treatment of FLT3-ITD-mutated myeloid leukemia
title_sort cd52 is a novel target for the treatment of flt3-itd-mutated myeloid leukemia
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8149417/
https://www.ncbi.nlm.nih.gov/pubmed/34035227
http://dx.doi.org/10.1038/s41420-021-00446-8
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