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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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Detalles Bibliográficos
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
Descripción
Sumario: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.