Histone deacetylase inhibitor treatment downregulates VLA-4 adhesion in hematopoietic stem cells and acute myeloid leukemia blast cells.
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.
Mahlknecht
Ulrich
U
Saarland University Medical Center Department of Immunotherapy and Gene Therapy, Kirrberger Strasse, Bldg. 4.3, D-66424 Homburg/Saar, Germany. ulrich.mahlknecht@uks.eu
Schönbein
Christiane
C
D000208:Acute Disease; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects*; D045744:Cell Line, Tumor / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D019650:Hematopoietic Stem Cell Mobilization; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D039041:Integrin alpha4beta1 / Q000096:biosynthesis* / Q000235:genetics; D007951:Leukemia, Myeloid / Q000473:pathology*; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D018365:Neoplasm, Residual / Q000517:prevention & control; D014411:Neoplastic Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D014635:Valproic Acid / Q000494:pharmacology*; D000077337:Vorinostat
D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D039041:Integrin alpha4beta1; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D000077337:Vorinostat; D014635:Valproic Acid