CD34+ marrow progenitors from MDS patients with high levels of intramedullary apoptosis have reduced expression of α4β1 and α5β1 integrins

Abstract

Excessive intramedullary apoptosis is central in the pathogenesis of myelodysplastic syndromes (MDS). Growth-inhibiting cytokines, the Fas/FasLigand pathway, and autoreactive cytotoxic T-lymphocytes have been identified to be important proapoptotic factors in MDS. In normal hematopoiesis, a4b1 and a5b1 integrin-mediated interactions between progenitors and fibronectin are critical for progenitor cell survival. In this study, we have used flow cytometry to quantify the expression levels of members of the b1 integrin family on CD34 þ marrow progenitors in 27 untreated patients with MDS, three with s-AML, and 25 control subjects. In MDS, we observed that nonapoptotic progenitors significantly downregulate cell surface expression levels of a4 and b1 integrin chains compared with healthy controls. Downregulation of a4, b1, and also a5 was present in MDS patients with Z25% apoptotic progenitors, irrespective of their French, American, British subcategory. Reduced cell surface expression levels of a4, a5, and b1 did also correlate with decreased in vitro adhesiveness to fibronectin fragments. Therefore, our observations suggest that downregulation of a4b1 and a5b1 integrins on CD34 þ progenitors could be a newly identified proapoptotic mechanism in MDS.

Very late antigen-4 function of myeloblasts correlates with improved overall survival for patients with acute myeloid leukemia

“…Other investigators have had similar results with these antibody clones, in that there was always higher ␣ 4 expression than ␤ 1 expression for the same cell populations. 27 Other ␣ integrin partners with ␤ 1 (eg, ␣ 1 , ␣ 2 , ␣ 3 , ␣ 5 , ␣ 6 ) are minimally expressed by myeloid cells, and the alternative partner of ␣ 4 , ␤ 7 , occurs mainly in lymphoid cells with tropism for the gastrointestinal tract.…”

CXCR4 antagonists: targeting the microenvironment in leukemia and other cancers

“…106 Adhesion molecules, in particular the very late antigen-4 (VLA-4) integrins, along with CXCR4 chemokine receptors, are essential for AML cell adhesion to respective ligands (fibronectin and VCAM-1) on stromal cells 107 and for protection of AML cells from spontaneous or drug-induced apoptosis. 106,108 CXCR4 receptors are functional in AML, 58,109 and surface CXCR4 expression, which is generally low when compared with lymphoid cells, correlates with functional responses, such as chemotaxis. 110 CXCR4-dependent engraftment of AML cells in non-obese diabetic/severe combined immunodeficient (NOD/SCID) mice was demonstrated by Tavor et al, 111 and this group also reported that the proteolytic enzyme elastase is involved in regulating SDF-1-dependent migration and proliferation of AML cells in vitro and in vivo.…”

Multipotent adult progenitor cells improve the hematopoietic function in myelodysplasia

“…The etiology of bone marrow (BM) failure in MDS is not yet fully understood but is multifactorial and caused by intrinsic defects in the HSC (e.g., mutations in AML1, EVI1, NUP98 and NUP214) as well as extrinsic defects in the BM niche [3]. The latter include excess production of, for example, tumor necrosis factor-α and interferon-γ, abnormalities in endothelial cells, mesenchymal stromal cells (MSCs) and osteoblasts (cells that are part of the HSC niche) and activation of T lymphocytes, monocytes and dendritic cells leading to abnormal proliferation and differentiation of HSCs [4][5][6][7][8][9].The only curative therapy is allogeneic HSC transplantation, which is suitable for only a minority of the patients due to advanced age. Recently, three drugs have been approved by the U.S. Food and Drug Administration: decitabine, lenalidomide and 5-azacitidine (the last two are also approved by the European Medicines Agency); in a subgroup of MDS patients, these drugs decrease cytopenias, induce cytogenetic remission and reduce BM blasts, while not completely eradicating the malignant HSC clone [10].…”