Abstract
The alpha4beta1 integrin very late activation antigen-4 (VLA-4) is an alpha4 (CD49d)/beta1 (CD29) heterodimer. It plays a key role in the adhesion of both hematopoietic progenitor cells and leukemic blast cells to bone marrow stromal cells which express the vascular cell adhesion molecule-1 (VCAM-1) or produce fibronectin. VLA-4 expression has been associated with bone-marrow minimal residual disease, which causes relapse after chemotherapy in patients with acute myelogenous leukemia. Conversely, the absence of VLA-4 reduces bone marrow retention of both hematopoietic progenitor and leukemic blast cells. We report on the downregulation of VLA-4/CD49d for various acute myelogenous leukemia cells lines, on primary cells from patients with acute myelogenous leukemia, and on hematopoietic stem cells and peripheral blood mononuclear cells from healthy donors on treatment with the histone deacetylase inhibitors suberoylanilide hydroxamic acid and valproic acid, which is associated with decreased adhesion to mesenchymal stromal cells. These findings suggest that HDAC-inhibitor treatment may on the one hand impair stem cell homing, while on the other it may improve peripheral blood stem cell mobilization and significantly help to reduce minimal residual disease from acute myelogenous leukemia.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acute Disease
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Bone Marrow Cells / cytology
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Bone Marrow Cells / drug effects
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Bone Marrow Cells / metabolism
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Cell Adhesion / drug effects*
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Cell Line, Tumor / cytology
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Cell Line, Tumor / drug effects
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Cell Line, Tumor / metabolism
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Cell Movement / drug effects
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Down-Regulation / drug effects
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Drug Screening Assays, Antitumor
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Hematopoietic Stem Cell Mobilization
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Hematopoietic Stem Cells / cytology
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Hematopoietic Stem Cells / drug effects*
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Hematopoietic Stem Cells / metabolism
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Histone Deacetylase Inhibitors*
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Humans
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Hydroxamic Acids / pharmacology*
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Integrin alpha4beta1 / biosynthesis*
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Integrin alpha4beta1 / genetics
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Leukemia, Myeloid / pathology*
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Leukocytes, Mononuclear / cytology
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Leukocytes, Mononuclear / drug effects
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Leukocytes, Mononuclear / metabolism
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Neoplasm Proteins / antagonists & inhibitors
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Neoplasm Proteins / biosynthesis
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Neoplasm Proteins / genetics
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Neoplasm, Residual / prevention & control
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Neoplastic Stem Cells / cytology
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Neoplastic Stem Cells / drug effects*
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Neoplastic Stem Cells / metabolism
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RNA, Messenger / biosynthesis
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RNA, Messenger / genetics
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RNA, Neoplasm / biosynthesis
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RNA, Neoplasm / genetics
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Valproic Acid / pharmacology*
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Vorinostat
Substances
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Histone Deacetylase Inhibitors
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Hydroxamic Acids
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Integrin alpha4beta1
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Neoplasm Proteins
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RNA, Messenger
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RNA, Neoplasm
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Vorinostat
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Valproic Acid