期刊
BLOOD
卷 121, 期 10, 页码 1814-1818出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2012-01-406272
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资金
- Nautica Triathlon Foundation
- Hyundai Hope on Wheels Foundation
- St. Baldrick's Foundation
- LOEWE OSF TP5a
- Deutsche Forschungsgemeinschaft [BO3553/1-1]
- National Institutes of Health [R01CA137060, R01CA139032, R01CA157644]
Bone marrow (BM) provides chemoprotection for acute lymphoblastic leukemia (ALL) cells, contributing to lack of efficacy of current therapies. Integrin alpha4 (alpha4) mediates stromal adhesion of normal and malignant B-cell precursors, and according to gene expression analyses from 207 children with minimal residual disease, is highly associated with poorest outcome. We tested whether interference with alpha4-mediated stromal adhesion might be a new ALL treatment. Two models of leukemia were used, one genetic (conditional alpha4 ablation of BCR-ABL1 [p210(+)] leukemia) and one pharmacological (anti-functional alpha4 antibody treatment of primary ALL). Conditional deletion of alpha4 sensitized leukemia cell to nilotinib. Adhesion of primary pre-B ALL cells was alpha4-dependent; alpha4 blockade sensitized primary ALL cells toward chemotherapy. Chemotherapy combined with Natalizumab prolonged survival of NOD/SCID recipients of primary ALL, suggesting adjuvant alpha4 inhibition as a novel strategy for pre-B ALL.
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