Abstract
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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1082-1093 |
| Number of pages | 12 |
| Journal | Journal of Molecular Biology |
| Volume | 377 |
| Issue number | 4 |
| DOIs | |
| State | Published - Apr 4 2008 |
| Externally published | Yes |
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Keywords
- atomic force microscopy
- BCR/ABL
- bone marrow stromal cells
- cell adhesion
- chronic myeloid leukemia
ASJC Scopus subject areas
- Virology
Cite this
BCR/ABL Expression of Myeloid Progenitors Increases β1-Integrin Mediated Adhesion to Stromal Cells. / Fierro, Fernando A; Taubenberger, Anna; Puech, Pierre Henri; Ehninger, Gerhard; Bornhauser, Martin; Muller, Daniel J.; Illmer, Thomas.
In: Journal of Molecular Biology, Vol. 377, No. 4, 04.04.2008, p. 1082-1093.Research output: Contribution to journal › Article
}
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 -