Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antibodies, Monoclonal, Humanized / pharmacology*
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Bone Marrow / drug effects
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Bone Marrow / metabolism
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Bone Marrow / pathology
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Cell Adhesion
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Child
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Drug Resistance, Neoplasm*
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Flow Cytometry
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Fusion Proteins, bcr-abl / physiology*
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Humans
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Integrases / metabolism
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Integrin alpha4 / chemistry*
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Integrin alpha4 / genetics
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Integrin alpha4 / metabolism
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Mice
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Mice, Inbred NOD
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Mice, Knockout
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Mice, SCID
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Natalizumab
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Neoplasm, Residual / drug therapy*
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Neoplasm, Residual / metabolism
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Neoplasm, Residual / mortality
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Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / drug therapy*
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Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / metabolism
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Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / mortality
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RNA, Messenger / genetics
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Real-Time Polymerase Chain Reaction
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Reverse Transcriptase Polymerase Chain Reaction
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Stromal Cells / drug effects
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Stromal Cells / metabolism
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Stromal Cells / pathology
Substances
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Antibodies, Monoclonal, Humanized
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Natalizumab
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RNA, Messenger
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Integrin alpha4
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Fusion Proteins, bcr-abl
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Cre recombinase
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Integrases