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

• Published in: Cell death discovery 2021-05, Vol.7 (1), p.121-121, Article 121
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: 631/67/1990/283/1897; 692/53/2422; Acute myeloid leukemia; AKT protein; Antibody-dependent cell-mediated cytotoxicity; Antitumor activity; Apoptosis; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Cycle Analysis; CRISPR; Cytotoxicity; DNA microarrays; Flow cytometry; Flt3 protein; Leukemia; Life Sciences; Monoclonal antibodies; Myeloid leukemia; Protein-tyrosine kinase; Stat5 protein; Stem Cells; Xenografts
• ISSN: 2058-7716; 2058-7716
• DOI: 10.1038/s41420-021-00446-8

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.