Novel chimaeric protein expressed in Philadelphia positive acute lymphoblastic leukaemia

Abstract

Cytogenic changes are becoming increasingly important in understanding the pathogenesis of human malignancies. The t(9;22) (q34;q11) translocation is one of the most consistent and generates the Philadelphia chromosome (Ph1) (ref. 1) in chronic myeloid leukaemia (CML); it has also been observed in some acute lymphoblastic leukaemias (ALL) (ref. 2). In CML the breakpoints occur on chromosome 22 in the region designated bcr (ref. 3) and result in the expression of a bcr-abl fusion product of relative molecular mass (MT) 210,000 (210K) with associated in vitro tyrosine kinase activity (P210bcr-abl). In some cases of Ph1-positive ALL, a novel abl-related protein (P190all-abl) of 190K has been shown to have tyrosine kinase activity. In this report we demonstrate that the P190all-abl protein has a bcr determinant from the amino-terminal region, but is lacking a bcr determinant normally found in the P210bcr-abl near the bcr-abl junction. The chimaeric nature of the P190all-abl was confirmed by sequential immunoprecipitation with antisera against abl and bcr peptides.

BCR/ABL induces multiple abnormalities of cytoskeletal function.

“…An alternative breakpoint in BCR results in the formation , usually associated with Ph(ϩ) ALL (25). The kinase activity of p190 BCR/ABL is also elevated (26).…”

p38 MAPK-mediated activation of NF-κB by the RhoGEF domain of Bcr

“…Most chronic myelogenous leukemias (CML), and a subset of the acute lymphocytic leukemias (ALL), can be attributed to the aberrant expression of fusion proteins that encode amino terminal sequences from Bcr and carboxyl terminal sequences from the oncogenic nonreceptor tyrosine kinase Abl (Chan et al, 1987;Clark et al, 1988;Fainstein et al, 1987;Konopka et al, 1984;Kurzrock et al, 1987;Walker et al, 1987). Although animal models suggest that elevated levels of Abl tyrosine kinase activity contribute to Bcr-Abl mediated leukemogenesis (Lugo et al, 1990), the residues that distinguish the rearrangements associated with ALL (p185 Bcr-Abl) from the rearrangements associated with CML (p210 Bcr-Abl) reside within the Bcr protein.…”

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.…”