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
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.