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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.

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