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Histone deacetylase inhibitor treatment downregulates VLA-4 adhesion in hematopoietic stem cells and acute myeloid leukemia blast cells

Saarland University Medical Center, Department of Immunotherapy and Gene Therapy, Homburg/Saar; Department of Hematology/Oncology, University of Heidelberg Medical Center, Heidelberg, Germany

Correspondence: Ulrich Mahlknecht, Saarland University Medical Center Department of Immunotherapy and Gene Therapy, Kirrberger Straße, Bldg. 4.3, D-66424 Homburg/Saar, Germany. E-mail: ulrich.mahlknecht{at}uks.eu

The 4β1 integrin very late activation antigen-4 (VLA-4) is an 4 (CD49d)/β1 (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.

Key words: homing, adhesion, histone deacetylase, stem cell transplantation, minimal residual disease.