A novel c-abl protein product in Philadelphia-positive acute lymphoblastic leukaemia

Abstract

Activation of cellular proto-oncogenes as a result of chromosomal abnormalities has been implicated in the development of some human malignancies. Perhaps one of the most striking examples of this association occurs in chronic myelogenous leukaemia, where the Philadelphia (Ph) translocation results in substitution of the 5' end of the c-abl proto-oncogene with bcr gene sequences. A unique hybrid bcr-abl message is produced. As the Ph translocation is also present in some patients with acute lymphoblastic leukaemia, we initiated studies to determine if similar genomic events occur in these two different forms of Ph-positive leukaemia. Here we report that the Ph translocation in acute lymphoblastic leukaemia can result in production of a novel aberrant c-abl protein that is distinct from the bcr-abl protein found in Ph-positive chronic myelogenous leukaemia. Our observations suggest that alternative mechanisms of activation of c-abl exist, and may be important in the development of human acute lymphoid rather than chronic myeloid malignancies.

Bcr phosphorylated on tyrosine 177 binds Grb2

“…The resulting BcrAbl proteins are termed P185 BCR-ABL or P210 BCR-ABL. Unlike the normal Abl protein, both BcrAbl proteins possess an activated tyrosine protein kinase activity (Konopka et al, 1984;Kloetzer et al, 1985;Kurzrock et al, 1987).…”

True

“…20,21 In P210 BCR-ABL this N-terminal variable region is replaced by the N-terminal 902 amino acids of BCR ( Figure 1). A related fusion protein, P190 BCR-ABL , contains the N-terminal 426 amino acids of BCR and is found in Philadelphia chromosome positive (Ph + ) acute lymphocytic leukemia (ALL) [3][4][5] (Figure 1). The product of both BCR-ABL chimeric…”

“…1,2 The product of BCR-ABL gene is usually a chimeric BCR-ABL protein of either 210 kDa or 190 kDa associated, respectively, with CML and acute lymphocytic leukemia (ALL). [2][3][4][5] A much rarer third species of 230 kDa that may be preferentially associated with a milder form of CML has recently been identified. [6][7][8][9] The CML stem cell generates a dominant multilineage clone which overproduces all hematopoietic progenitors (colony-forming cells, CFCs) as well as more differentiated granulocytes.…”

Sustained leukaemic phenotype after inactivation of BCR-ABLp190 in mice

“…Imatinib is a moderately potent inhibitor of the kinase BCRABLp210, the fusion protein product of a chromosomal translocation, named Philadelphia chromosome (Ph), which is involved in the pathogenesis of chronic myeloid leukaemia (CML) (Druker et al, 2001a;Mauro and Druker, 2001;O'Dwyer and Druker, 2001;Chabner and Roberts, 2005) and of the BCR-ABLp190 product, which is mainly associated with B-cell acute lymphoblastic leukaemia (B-ALL) (Chan et al, 1987;Clark et al, 1987;Hermans et al, 1987;Kurzrock et al, 1987;Melo, 1996). It has been shown that when imatinib is used to treat patients with chronic-phase CML, 90% seem to achieve complete haematological remission and many lose cytogenetic evidence of the malignant clone (Druker et al, 2001a).…”