BCR/ABL Expression of Myeloid Progenitors Increases beta sub(1)-Integrin Mediated Adhesion to Stromal Cells

The expression of the fusion protein BCR/ABL is a hallmark of chronic myeloid leukemia. BCR/ABL is a constitutively active tyrosine kinase influencing cell proliferation, apoptosis, and differentiation. To what extent and by which mechanism BCR/ABL affects the adhesion of leukemic cells to bone marr...

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Veröffentlicht in:Journal of molecular biology 2008-04, Vol.377 (4), p.1082-1093
Hauptverfasser: Fierro, F A, Taubenberger, A, Puech, PH, Ehninger, G, Bornhauser, M, Muller, D J, Illmer, T
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Sprache:eng
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Zusammenfassung:The expression of the fusion protein BCR/ABL is a hallmark of chronic myeloid leukemia. BCR/ABL is a constitutively active tyrosine kinase influencing cell proliferation, apoptosis, and differentiation. To what extent and by which mechanism BCR/ABL affects the adhesion of leukemic cells to bone marrow stromal cells (BMSC) is controversial. To characterize adhesion of BCR /ABL-transformed 32D cells (32D-BCR/ABL) to the BMSC line M2-10B4, we used washing assays and single-cell force spectroscopy (SCFS). Compared to control 32D cells (32D-V), 32D-BCR/ABL developed threefold higher adhesion forces. This enhanced cell adhesion could be reduced to control levels after specifically inhibiting the activity of the tyrosine kinase BCR/ABL using imatinib mesylate (IM). SCFS showed that the adhesion forces of 32D-BCR/ABL were strongest to fibronectin and collagen type I, suggesting that beta sub(1)-integrin has a major role in mediating the adhesion of leukemic cells to BMSC. Indeed, the beta sub(1)-integrin blocking antibody Ha2/5 abrogated the attachment of 32D-V and 32D-BCR/ABL cells to BMSC. Although 32D-BCR/ABL cells show significantly increased beta sub(1)-integrin expression, no significant difference of beta sub(1)-integrin mRNA levels could be detected, indicating a post-transcriptional regulation of beta sub(1)-comprising integrin heterodimers by BCR/ABL. The data presented here argue that the interaction of beta sub(1)-integrin and extracellular matrix components is functionally important in leukemic cells expressing high-levels of BCR/ABL, and could provide a rationale for the development of optimized targeted therapies.
ISSN:0022-2836
DOI:10.1016/j.jmb.2008.01.085