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


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Article Info

DATE

2021-05-25

AUTHORS

Sivasundaram Karnan, Ichiro Hanamura, Akinobu Ota, Souichi Takasugi, Ayano Nakamura, Miyuki Takahashi, Kaori Uchino, Satsuki Murakami, Md Wahiduzzaman, Lam Quang Vu, Md Lutfur Rahman, Muhammad Nazmul Hasan, Toshinori Hyodo, Hiroyuki Konishi, Shinobu Tsuzuki, Kazuhiro Yoshikawa, Susumu Suzuki, Ryuzo Ueda, Masayuki Ejiri, Yoshitaka Hosokawa, Akiyoshi Takami

ABSTRACT

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 FLT3ITD/WT cells using the CRISPR-Cas9 system in a human myeloid leukemia cell line, K562. cDNA microarray analysis revealed elevated CD52 expression in K562-FLT3ITD/WT cells compared to K562-FLT3WT/WT cells, an observation that was further confirmed by quantitative real-time-PCR and flow cytometric analyses. The elevated expression of CD52 in K562-FLT3ITD/WT cells was decreased in wild-type FLT3 (FLT3-WT) knock-in K562-FLT3ITD/WT cells. In K562-FLT3ITD/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-FLT3ITD/WT cells compared to K562-FLT3WT/WT cells. Furthermore, alemtuzumab significantly suppressed the xenograft tumor growth of K562-FLT3ITD/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-FLT3ITD/WT cells. Our findings may allow establishment of a new therapeutic option, alemtuzumab, to treat leukemia with the FLT3-ITD mutation. More... »

PAGES

121

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/s41420-021-00446-8

DOI

http://dx.doi.org/10.1038/s41420-021-00446-8

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1138324701

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/34035227


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