Cancer Therapy: Clinical Identification of Campath-1 (CD52) as Novel Drug Target in Neoplastic Stem Cells in 5q-Patients with MDS and AML

Purpose: The CD52-targeted antibody alemtuzumab induces major clinical responses in a group of patients with myelodysplastic syndromes (MDS). The mechanism underlying this drug effect remains unknown. Experimental Design:We asked whether neoplastic stem cells (NSC) in patients with MDS (n1⁄4 29) or acute myelogenous leukemia (AML; n 1⁄4 62) express CD52. Results: As assessed by flow cytometry, CD52 was found to be expressed on NSC-enriched CD34þ/CD38 cells in 8/11 patients with MDS and isolated del(5q). In most other patients with MDS, CD52was weakly expressed or not detectable onNSC. In AML, CD34þ/CD38 cells displayed CD52 in 23/ 62 patients, including four with complex karyotype and del(5q) and one with del(5q) and t(1;17;X). In quantitative PCR (qPCR) analyses, purified NSC obtained from del(5q) patients expressed CD52 mRNA. Wewere also able to show thatCD52mRNA levels correlatewith EVI1 expression and thatNRAS induces the expression of CD52 in AML cells. The CD52-targeting drug alemtuzumab, was found to induce complement-dependent lysis of CD34þ/CD38 /CD52þ NSC, but did not induce lysis in CD52 NSC. Alemtuzumab also suppressed engraftment of CD52þ NSC in NSG mice. Finally, CD52 expression on NSC was found to correlate with a poor survival in patients with MDS and AML. Conclusions: The cell surface target Campath-1 (CD52) is expressed on NSC in a group of patients with MDS and AML. CD52 is a novel prognostic NSC marker and a potential NSC target in a subset of patients with MDS and AML, which may have clinical implications and may explain clinical effects produced by alemtuzumab in these patients. Clin Cancer Res; 20(13); 3589–602. 2014 AACR.