CD58-Negtive Leukemia Initiating Cells Are Independently Associated with High Risk of Relapse in B-Precursor Acute Lymphoblastic Leukemia: A Comprehensive Clinical and Biological Profiling Study

Using neonatal NOD/SCID/IL2rγ^null xenotransplantation model, we previously demonstrated that CD34⁺CD38⁺CD19⁺ cells as well as CD34⁺CD38⁻CD19⁺ cells have the capacities to initiate B-precursor ALL (B-ALL) in vivo and to self-renew, that is, leukemia initiating cells(LICs) are enriched in the CD34⁺CD19⁺phenotype in human B-ALL (Kong Y et al. Leukemia 2008; 22: 1207–1213). Nevertheless, in order to distinguish B-ALL initiating cells from their normal compartment, further markers have to be identified. CD58 (lymphocyte function–associated antigen 3), a cell surface adhesion molecule binding to CD2, plays a critical role in the attachment of cytotoxic T lymphocytes and non-specific killer cells to their targets. Recent data give evidence that diffuse large B cell lymphoma patients with poor expression of CD58 appear to be more aggressive by escaping from immune-surveillance of the host. However, the prognostic relevance of CD58 expression on B-ALL initiating cells is largely unknown.

To investigate the expression profile of CD58 on CD34⁺CD19⁺B-ALL initiating cells. To evaluate the prognostic significance of CD58 expression on LICs in human B-precursor ALL.

Using a cohort of 139 patients (including pediatric and adult patients) with CD34⁺ B-ALL, the expression profile of CD58 on LICs(CD34⁺CD19⁺ phenotype) were examined by multicolor flow cytometry (FCM) at diagnosis. A total of 1,050,000 events were routinely collected. More than 20% of LICs with CD58 expression were defined as CD58-positive LICs (CD34⁺CD19⁺CD58⁺ phenotype, abbreviated by CD58⁺LICs), all other cases were defined as CD58-negtive LICs (CD34⁺CD19⁺CD58⁻phenotype, abbreviated by CD58⁻LICs). Furthermore, the impact of CD58⁻LICs at diagnosis on the clinical outcome was prospectively investigated. The study was approved by the Ethics Committee of Peking University People's Hospital and written informed consent was obtained from all subjects.

Among the newly diagnosed B-ALL patients, 119 cases were detected with CD58⁺LICs and the remaining 20 cases with CD58⁻LICs. The expression of CD58 on LICs at diagnosis was inversely related to the age, WBC at diagnosis and NCCN risk group of the B-ALL patients (P=0.002, P=0.015 and P=0.009, respectively). CD58⁺LICs group had a higher complete remission(CR) rate after one course induction than CD58⁻LICs group (87.39% vs. 65.00%, P=0.019).Cumulative incidence of relapse (CIR) at 2-year in the CD58⁺LICs group was significantly lower than that in the CD58⁻LICs group (18.20% ± 0.15% vs. 72.00% ± 1.30%, P<0.0001). CD58⁺LICs group resulted in superior survival compared to CD58⁻LICs group (2-year disease-free survival(DFS), 77.95% ± 4.36% vs. 28.00% ± 10.58%, P<0.0001; 2-year overall survival(OS), 75.61% ± 5.53% vs. 42.4% ± 11.50%, P = 0.0016). Multivariate analysis revealed CD58⁻LICs at diagnosis as independent risk factor affecting relapse (HR=3.413, P=0.001) and DFS (HR=2.857, P=0.004) in B-ALL patients. By summing up the risk factors(RF) defined as CD58 status on LICs (CD58⁺LICs=0,CD58⁻LICs=1),age(<18 years=0,≥18 years=1) and NCCN risk group (Standard risk=0, High risk=1), two prognostic groups (Low risk group: RF≤1;High risk group: RF>1)could be discriminated, which differed significantly with regard to 2-year CIR(9.18%±0.14% vs. 49.94%±0.67%, P<0.0001), 2-year DFS (90.82%±5.65% vs. 39.83%±7.97%, P<0.0001) and 2-year OS(91.21%±3.87% vs. 45.27%±7.89%, P<0.0001), respectively.

CD58-negtive leukemia initiating cells at diagnosis independently correlate with unfavorable prognosis. Combined analysis of CD58 status on CD34⁺CD19⁺leukemia initiating cells at diagnosis, age and NCCN risk group may help to optimize currently available prognostic stratification model in B-ALL.

This work was supported by grants from National Natural Science Foundation of China (30800483) and Beijing Municipal Science and Technology Program (Z111107067311070).

No relevant conflicts of interest to declare.