CD9 blockade suppresses disease progression of high-risk pediatric B-cell precursor acute lymphoblastic leukemia and enhances chemosensitivity
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AbstractCD9 has been implicated in cancer progression but its prognostic relevance and therapeutic potential in B-cell precursor acute lymphoblastic leukemia (BCP-ALL) are largely unknown. In a cohort of pediatric BCP-ALL patients, we found that CD9+ cases had a significantly lower 5-year relapse-free survival rate than CD9- cases. Multivariate analysis demonstrated that CD9 positivity independently predicted inferior survival outcomes, and could be applied with established prognostic features, including prednisone response and cytogenetic status, to refine patient stratification. Administration of CD9 antibody substantially suppressed disease progression in NOD/SCID mice xenografted with CD9+ cell lines and primary leukemic blasts from patients with high-risk and refractory BCP-ALL, without compromising hematopoietic stem cell engraftment. Combination of anti-CD9 with conventional chemotherapy further reduced leukemic burden and prolonged animal survival. Mechanistically, CD9 blockade inhibited leukemic cell proliferation, induced G0/G1 cell cycle arrest, activated p38, and enhanced chemotherapeutic agent-induced apoptosis. Further, CD9 physically interacted with integrin very late antigen-4, regulated affinity to vascular cell adhesion molecule-1, and was involved in leukemia-stroma interaction. Collectively, our study established CD9 as a new prognostic marker, validated the preclinical efficacy of CD9 antibody, and laid the foundation for clinical development of CD9-targeted therapy for high-risk and refractory pediatric BCP-ALL.
Acceptance Date15/08/2019
All Author(s) ListKam Tong Leung, Chi Zhang, Kathy Yuen Yee Chan, Karen Li, John Tak Kit Cheung, Margaret Heung Ling Ng, Xiao-Bing Zhang, Tony Sit, Wayne Yuk Wai Lee, Wei Kang, Ka Fai To, Jasmine Wai Sum Yu, Toni Ki Fong Man, Han Wang, Kam Sze Tsang, Frankie Wai Tsoi Cheng, Grace Kee See Lam, Tin Wai Chow, Alex Wing Kwan Leung, Ting Fan Leung, Patrick Man Pan Yuen, Pak Cheung Ng, Chi Kong Li
Journal nameLeukemia
Year2020
Month3
Volume Number34
Issue Number3
PublisherSpringer
Pages709 - 720
ISSN0887-6924
eISSN1476-5551
LanguagesEnglish-United Kingdom

Last updated on 2020-02-08 at 00:49