CD34+CD38-CD58- Candidate Leukemia-Initiating Cells Are Clinically Relevant With The Unfavorable Prognosis In Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia

The prognosis of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) has been greatly improved in the modern era of imatinib. Nevertheless, relapse is still a major cause of treatment failure in human Ph+ALL. Leukemia-initiating cells (LICs) are presumed to be responsible for relapse in leukemia. Therefore, we conducted a study to identify the candidate LICs that are responsible for disease progression and its clinical significance in patients with Ph+ALL.To investigate the leukemia-initiating and self-renewal capacities of CD34+CD38-CD58- cells and determine the prognostic significance of CD34+CD38-CD58- phenotype in patients with Ph+ALL treated in Peking University Institute of Hematology.The leukemia-initiating potential and self-renewal capacity of the sorted CD34+CD38-CD58-, CD34+CD38-CD58+,CD34+CD38+CD58- and CD34+CD38+CD58+ compartments were investigated in vivo using sublethally irradiated and anti-mouse CD122 monoclonal antibody conditioned NOD/SCID mice by intra-bone marrow–injection. Furthermore, we prospectively analyzed whether the identified CD34+CD38-CD58- compartment at diagnosis correlates with minimal residual disease (MRD) after therapy and clinical outcomes in 63 adult patients (18-60 years) with de novo Ph+ALL.Xenotransplantation of the sorted CD34+CD38-CD58- cells led to a repopulation of human B-ALL in primary and secondary recipient mice, which were phenotypically and clonally derived from the original Ph+ALL patients analyzed by flow cytometry, as well as quantitative real-time RT-PCR and fluorescence in situ hybridization for leukemia-specific cytogenetic abnormalities. Furthermore, the candidate CD34+CD38-CD58- LICs phenotype at diagnosis (n=16) significantly correlated with a lower complete remission rate and higher MRD frequency monitored by BCR-ABL mRNA levels in BM of Ph+ALL patients. Additionally, it directly correlated with higher cumulative incidence of relapse (CIR, 60% ± 1.97% vs. 15.51% ± 0.30%, P=0.002) and unfavorable disease-free survival (DFS, 33.75%±12.64% vs. 71.31%±7.17%, P=0.009) at 3-year. The CD34+CD38-CD58- group exhibited a higher rate of BCR-ABL mutations conferring higher level imatinib resistance than the other group (43.75% vs. 17.02%, P=0.04). Multivariate analyses revealed that CD34+CD38-CD58- phenotype at diagnosis was an independent risk factor for relapse (HR=4.35, P=0.009) and DFS (HR=3.38, P=0.008) in adult Ph+ALL.Both the xenotransplantation data as well as the clinical correlation studies show that CD34+CD38-CD58- compartment enrich for leukemia-initiating cells in adult Ph+ALL. CD34+CD38-CD58- phenotype at diagnosis independently correlates with an adverse prognosis, which promises to be an efficient tool for relapse prediction and risk-stratification treatment in adult Ph+ALL patients.This work was supported by grants from National Natural Science Foundation of China (grants no. 30800483&81230013) and Beijing Municipal Science and Technology Program (grant no.Z111107067311070).No relevant conflicts of interest to declare.