Authors' Affiliations: Department of Internal Medicine I, Division of Hematology & Hemostaseology, Medical University of Vienna, Austria;
Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Austria;
Clin Cancer Res. 2014 Jul 1;20(13):3589-602. doi: 10.1158/1078-0432.CCR-13-2811. Epub 2014 May 5.
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.
We asked whether neoplastic stem cells (NSC) in patients with MDS (n = 29) or acute myelogenous leukemia (AML; n = 62) express CD52.
As assessed by flow cytometry, CD52 was found to be expressed on NSC-enriched CD34(+)/CD38(-) cells in 8/11 patients with MDS and isolated del(5q). In most other patients with MDS, CD52 was weakly expressed or not detectable on NSC. In AML, CD34(+)/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. We were also able to show that CD52 mRNA levels correlate with EVI1 expression and that NRAS induces the expression of CD52 in AML cells. The CD52-targeting drug alemtuzumab, was found to induce complement-dependent lysis of CD34(+)/CD38(-)/CD52(+) NSC, but did not induce lysis in CD52(-) NSC. Alemtuzumab also suppressed engraftment of CD52(+) NSC in NSG mice. Finally, CD52 expression on NSC was found to correlate with a poor survival in patients with MDS and AML.
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.
靶向 CD52 的抗体阿仑单抗可诱导一组骨髓增生异常综合征（MDS）患者产生主要临床反应。这种药物作用的机制尚不清楚。
我们询问了 MDS（n=29）或急性髓性白血病（AML；n=62）患者的肿瘤干细胞（NSC）是否表达 CD52。
流式细胞术检测发现，11 例 MDS 患者中有 8 例（孤立 del(5q)）和富含 NSC 的 CD34(+)/CD38(-)细胞表达 CD52。在大多数其他 MDS 患者中，NSC 上 CD52 的表达较弱或无法检测到。在 AML 中，23/62 例患者的 CD34(+)/CD38(-)细胞表达 CD52，包括 4 例具有复杂核型和 del(5q)、1 例具有 del(5q)和 t(1;17;X)。在定量 PCR (qPCR)分析中，从 del(5q)患者中分离出的纯化 NSC 表达 CD52 mRNA。我们还能够证明 CD52 mRNA 水平与 EVI1 表达相关，并且 NRAS 可诱导 AML 细胞表达 CD52。CD52 靶向药物阿仑单抗被发现可诱导 CD34(+)/CD38(-)/CD52(+) NSC 的补体依赖性裂解，但不能诱导 CD52(-) NSC 的裂解。阿仑单抗还抑制了 NSG 小鼠中 CD52(+) NSC 的植入。最后，在 MDS 和 AML 患者中，NSC 上的 CD52 表达与较差的生存相关。
细胞表面靶标 Campath-1（CD52）在一组 MDS 和 AML 患者的 NSC 上表达。CD52 是一种新的预后 NSC 标志物，也是 MDS 和 AML 患者中 NSC 的潜在靶点，这可能具有临床意义，并可解释阿仑单抗在这些患者中产生的临床效果。
