Role of abnormal integrin-cytoskeletal interactions in impaired beta 1 integrin function in chronic myelogenous leukemia hematopoietic progenitors

Citation
R. Bhatia et al., Role of abnormal integrin-cytoskeletal interactions in impaired beta 1 integrin function in chronic myelogenous leukemia hematopoietic progenitors, EXP HEMATOL, 27(9), 1999, pp. 1384-1396
Citations number
54
Categorie Soggetti
Cardiovascular & Hematology Research
Journal title
EXPERIMENTAL HEMATOLOGY
ISSN journal
0301472X → ACNP
Volume
27
Issue
9
Year of publication
1999
Pages
1384 - 1396
Database
ISI
SICI code
0301-472X(199909)27:9<1384:ROAIII>2.0.ZU;2-1
Abstract
Abnormal circulation and unregulated proliferation of chronic myelogenous l eukemia (CML) progenitors is related, at least in part, to BCR/ABL induced abnormalities in beta 1 integrin-mediated adhesion and signaling. The BCR/A BL oncogene has several potential interactions with cytoskeletal elements t hat are important for normal integrin signaling. In the present study, we e valuated whether abnormalities in beta 1 integrin-cytoskeletal interactions were present in primary CML progenitors and contributed to defective integ rin function. beta 1 integrin-cytoskeletal interactions were studied in CML and normal CD34(+) primary hematopoietic progenitors as well as BCR/ABL-tr ansfected or mock-transfected M07e cells. In normal CD34(+) progenitors, an tibody-mediated cross-linking of beta 1 integrins resulted in their redistr ibution into caps via a process requiring receptor-cytoskeletal interaction s. CML CD34(+) cells demonstrated significantly impaired beta 1 integrin ca pping. This defect was related to the presence of the BCR/ABL gene, because capping also was impaired in BCR/ABL-transfected M07e cells. Defective rec eptor capping was not seen for non-integrin receptors. In addition, CML CD3 4(+) and M07e(BCR/ABL) cells also demonstrated increased actin polymerizati on and altered actin cytoskeletal organization. Further studies suggested t hat impaired beta 1 integrin capping and defective integrin-mediated adhesi on and proliferation inhibition in CML cells were related to abnormally enh anced integrin-cytoskeletal association and restricted receptor mobility. F inally, interferon or, which restores integrin-mediated adhesion and signal ing in CML progenitors, also enhanced integrin capping in CD34(+) cells. Th ese studies suggest that p210(BCR/ABL) induces abnormal association of inte grin receptors with the cytoskeleton and restricted receptor mobility and p rovide new insights into mechanisms underlying abnormal integrin function i n Chit progenitors. (C) 1999 International Society for Experimental Hematol ogy. Published by Elsevier Science Inc.