BCR/ABL expression of myeloid progenitors increases beta1-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 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 beta1-integrin has a major role in mediating the adhesion of leukemic cells to BMSC. Indeed, the beta1-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 beta1-integrin expression, no significant difference of beta1-integrin mRNA levels could be detected, indicating a post-transcriptional regulation of beta1-comprising integrin heterodimers by BCR/ABL. The data presented here argue that the interaction of beta1-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.
Fierro
Fernando A
FA
Medical Clinic and Policlinic I, Technical University, Dresden, Germany.
Taubenberger
Anna
A
Puech
Pierre-Henri
PH
Ehninger
Gerhard
G
Bornhauser
Martin
M
Muller
Daniel J
DJ
Illmer
Thomas
T
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001549:Benzamides; D002448:Cell Adhesion / Q000187:drug effects / Q000235:genetics*; D018929:Cell Culture Techniques; D002478:Cells, Cultured; D024042:Collagen Type I / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism; D016044:Fusion Proteins, bcr-abl / Q000235:genetics* / Q000502:physiology; D000068877:Imatinib Mesylate; D019012:Integrin beta1 / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D023461:Myeloid Progenitor Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D010879:Piperazines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D013997:Time Factors; D014162:Transfection
D000970:Antineoplastic Agents; D001549:Benzamides; D024042:Collagen Type I; D005353:Fibronectins; D019012:Integrin beta1; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl