TY - JOUR
T1 - BCR/ABL Expression of Myeloid Progenitors Increases β1-Integrin Mediated Adhesion to Stromal Cells
AU - Fierro, Fernando A
AU - Taubenberger, Anna
AU - Puech, Pierre Henri
AU - Ehninger, Gerhard
AU - Bornhauser, Martin
AU - Muller, Daniel J.
AU - Illmer, Thomas
PY - 2008/4/4
Y1 - 2008/4/4
N2 - 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 β1-integrin has a major role in mediating the adhesion of leukemic cells to BMSC. Indeed, the β1-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 β1-integrin expression, no significant difference of β1-integrin mRNA levels could be detected, indicating a post-transcriptional regulation of β1-comprising integrin heterodimers by BCR/ABL. The data presented here argue that the interaction of β1-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.
AB - 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 β1-integrin has a major role in mediating the adhesion of leukemic cells to BMSC. Indeed, the β1-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 β1-integrin expression, no significant difference of β1-integrin mRNA levels could be detected, indicating a post-transcriptional regulation of β1-comprising integrin heterodimers by BCR/ABL. The data presented here argue that the interaction of β1-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.
KW - atomic force microscopy
KW - BCR/ABL
KW - bone marrow stromal cells
KW - cell adhesion
KW - chronic myeloid leukemia
UR - http://www.scopus.com/inward/record.url?scp=40849120282&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=40849120282&partnerID=8YFLogxK
U2 - 10.1016/j.jmb.2008.01.085
DO - 10.1016/j.jmb.2008.01.085
M3 - Article
C2 - 18313694
AN - SCOPUS:40849120282
VL - 377
SP - 1082
EP - 1093
JO - Journal of Molecular Biology
JF - Journal of Molecular Biology
SN - 0022-2836
IS - 4
ER -