The tetraspanin CD9 is an adverse prognostic factor in pediatric B-precursor acute lymphoblastic leukemia and can be effectively targeted by neutralizing antibody in preclinical animal models
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摘要Background: B-precursor acute lymphoblastic leukemia (B-ALL) is the most common childhood malignancy. Despite advances in risk-directed chemotherapy, high-risk pediatric B-ALL remain associated with poor clinical outcomes, underscoring the need for development of novel targeted therapy. CD9 has been associated with metastasis and progression of various types of malignancies, but its prognostic relevance and therapeutic potential in pediatric B-ALL remain largely unknown.

Aims: This study was designed to (1) characterize the expression of CD9 in a cohort of pediatric B-ALL patients and its association with 5-year clinical outcomes; and (2) evaluate the efficacy of using a CD9 antibody for treatment of B-ALL in preclinical animal models.

Methods: Cell surface expression of CD9 on leukemic blasts in pediatric B-ALL patients was characterized by flow cytometry. The effects of targeting CD9 with a neutralizing antibody as a single agent or in combination with chemotherapy on inhibition of B-ALL progression were evaluated in the NOD/SCID mouse xenograft model.

Results: CD9+ patients had significantly lower overall and relapse-free survival (RFS) rates compared with CD9- cases. Subgroup analysis revealed remarkably poorer outcomes in CD9+ patients of the high-risk group. A similar trend was also observed in patients of the intermediate-risk group but not in the standard-risk group. In univariate analysis, CD9 positivity, age <1 year, white cell count ≥100 × 109/L and poor prednisone response were associated with lower RFS rate. In multivariate analysis, CD9 positivity remained as an independent prognostic factor for adverse survival outcomes. Administration of CD9 antibody substantially reduced leukemic burden and prolonged survival of animals xenografted with the intermediate-risk 697 (TCF3-PBX1+) and high-risk RS4;11 (MLL-AF4+), but not the standard-risk Reh (ETV6-RUNX1+) cell lines. Similarly, CD9 antibody treatment significantly decreased B-ALL progression in patient-derived xenografts with a wide spectrum of genetic and disease features, including TCF3-PBX1+ and MLL-AF4+cases and those with relapsed/refractory diseases. Importantly, CD9 antibody in combination with conventional chemotherapy consisting of vincristine, dexamethasone and L-asparaginase further prolonged animal survival, when compared to animals treated with CD9 antibody or chemotherapy alone.

Conclusions: Expression of CD9 in pediatric B-ALL patients was associated with adverse survival outcomes and could be used for refinement of clinical risk group stratification. CD9 blockade, in adjunct to chemotherapy, was highly effective for suppressing B-ALL progression in preclinical animal models and could be developed as a novel and promising strategy for treatment of high-risk pediatric B-ALL.
著者Chi Zhang, Chi Kong Li, Kathy Yuen Yee Chan, Alex Wing Kwan Leung, John Tak Kit Cheung, Frankie Wai Tsoi Cheng, Jasmine Wai Sum Yu, Karen Li, Pak Cheung Ng, Kam Tong Leung
會議名稱The 13th Congress of Asian Society for Pediatric Research
會議地點Hong Kong

上次更新時間 2018-08-10 於 17:31