BCR/ABL induces multiple abnormalities of cytoskeletal function.

Abstract

The BCR/ABL oncogene causes human chronic myelogenous leukemia (CML), a myeloproliferative disease characterized by massive expansion of hematopoietic progenitor cells and cells of the granulocyte lineage. When transfected into murine hematopoietic cell lines, BCR/ABL causes cytokine-independence and enhances viability. There is also growing evidence that p210 BCR/ABL affects cytoskeletal structure. p210 BCR/ABL binds to actin, and several cytoskeletal proteins are tyrosine phosphorylated by this oncoprotein. Also, at least one aspect of cytoskeletal function is abnormal, in that the affinity of ␤ 1 integrins for fibronectin is altered in CML cells. However, isolated changes in ␤ 1 integrin function would be unlikely to explain the clinical phenotype of CML. We used time-lapse video microscopy to study cell motility and cell morphology on extracellular cell matrix protein-coated surfaces of a series of cell lines before and after transformation by BCR/ABL . BCR/ABL was associated with a striking increase in spontaneous motility, membrane ruffling, formation of long actin extensions (filopodia) and accelerated the rate of protrusion and retraction of pseudopodia on fibronectin-coated surfaces. Also, while untransformed cells were sessile for long periods, BCR/ABLtransformed cells exhibited persistent motility, except for brief periods during cell division. Using cell lines transformed by a temperature-sensitive mutant of BCR/ABL, these kinetic abnormalities of cytoskeletal function were shown to require BCR/ABL tyrosine kinase activity. Similar abnormalities of cytoskeletal function on fibronectin-coated surfaces were observed when hematopoietic progenitor cells purified by CD34 selection from patients with CML were compared with CD34 positive cells from normal individuals. Interestingly, ␣ -interferon treatment was found to slowly revert the abnormal motility phenotype of BCR/ABL -transformed cells towards normal. The increase in spontaneous motility and other defects of cytoskeletal function described here will be useful biological markers of the functional effects of BCR/ABL in hematopoietic cells. ( J. Clin. Invest.

Dominant effects of the bcr-abl oncogene on Drosophila morphogenesis

“…Of related interest is the ®nding that in mammalian systems, Bcr-Abl is also observed to alter cytoskeletal function and cell adhesion. bcr-abl transformed cells have altered actin cytoskeletal structures, demonstrate abnormal cell motility on ®bronectin-coated surfaces, and contain a number of of focal adhesion associated proteins that are tyrosine phosphorylated by Bcr-Abl (Salgia et al, 1995b(Salgia et al, , 1997.…”

“…Two notable features of CML and Ph + ALL are the abnormal proliferation of progenitor stem cell clones and the premature release of primitive and committed malignant Ph + -positive myeloid progenitors from the bone marrow microenvironment and their subsequent appearance in the peripheral blood (reviewed by Verfaillie et al, 1997). Additional evidence that Bcr-Abl can alter cytoskeletal function comes from studies of Bcr-Abl transformed cell lines which exhibit altered cell motility and other defects of cytoskeletal function (Salgia et al, 1997). These observations implicate Bcr-Abl in cell proliferation, di erentiation, and adhesion pathways and indicate the existence of downstream targets of Bcr-Abl kinase.…”

Chronic myelogenous leukemia: too much or too little growth, or both?

“…20,21 Differences in the expression of adhesion receptors on CML and normal CD34 + cells have been described. 18 Furthermore, CML CD34 + adhere significantly less well to fibronectin than normal CD34 + cells 18,19 even though the integrin expression pattern on CML and normal CD34 + cells is similar suggesting that integrins are functionally abnormal. p210 BCR-ABL phosphorylates Fak, paxillin, tensin, p130 Cas and CRKL, 7,19 all known to play an important role in integrin-dependent focal contacts.…”

“…18 Furthermore, CML CD34 + adhere significantly less well to fibronectin than normal CD34 + cells 18,19 even though the integrin expression pattern on CML and normal CD34 + cells is similar suggesting that integrins are functionally abnormal. p210 BCR-ABL phosphorylates Fak, paxillin, tensin, p130 Cas and CRKL, 7,19 all known to play an important role in integrin-dependent focal contacts. 22 Constitutive phosphorylation of one or more of the focal contact-associated molecules may thus prevent their participation in integrinmediated signaling cascade.…”

“…A number of in vitro studies have shown that adhesion of CML progenitors to the microenvironment is defective. [17][18][19] Furthermore, transplantation of CML cells in xenogenic recipients favors engraftment of the Ph − benign progenitor pool, indicating that Ph + progenitors may adhere (home) poorly to the marrow microenvironment. 20,21 Differences in the expression of adhesion receptors on CML and normal CD34 + cells have been described.…”