Alternative forms of the BCR-ABL oncogene have quantitatively different potencies for stimulation of immature lymphoid cells.

Abstract

The Philadelphia chromosome (t9:22;q34:qll) is found in more than 90% of patients with chronic myelogenous leukemia, in 10 to 20% of patients with acute lymphocytic leukemia, and in 1 to 2% of patients with acute myelogenous leukemia. Alternative chimeric oncogenes are formed by splicing different sets of BCR gene exons on chromosome 22 across the translocation breakpoint to a common set ofABL oncogene sequences on chromosome 9. This results in an 8.7-kilobase mRNA that encodes the P210 BCR-ABL gene product commonly found in patients with chronic myelogenous leukemia or a 7.0-kilobase mRNA that produces the P185 BCR-ABL gene product found in most Philadeliphia chromosome-positive patients with acute lymphocytic leukemia. To compare the efficiency of growth stimulation by these two proteins, we derived cDNA clones for each with identical 5' and 3' untranslated regions and expressed them from retrovirus vectors. Matched stocks were compared for potency to transform immature B-lymphoid lineage precursors. The growth-stimulating effects of P185 for this cell type were found to be significantly greater than those of P210. Structural changes in BCR may regulate the effectiveness of the ABL tyrosine kinase function, as monitored by lymphocyte growth response. Changes in mitogenic potency may help to explain the more acute leukemic presentation usually associated with expression of the P185 BCR-ABL oncogene.

Dominant effects of the bcr-abl oncogene on Drosophila morphogenesis

“…A 949 nucleotide NotI-NcoI fragment of human abl from cDNA P18 (Fainstein et al, 1989), was joined to Drosophila abl cDNA at a conserved NcoI site located 47 codons into the Drosophila Abl protein tyrosine kinase domain as previously described . Next a 3 kb EagI ± KpnI fragment of P210 bcr-abl and 1.6 kb EagI ± KpnI fragment of P185 bcrabl from plasmid (-447 p210 pMV6tkNeo) and plasmid (-447 p185 pMV6tkNeo) respectively (from S Clark, University of Wisconsin) (McLaughlin et al, 1989), was ligated to a 5.3 kb KpnI ± NotI abl hu/¯y fragment from pBS abl hu/¯y . The P210 and P185 chimeric cDNA sequences contain 10 nucleotides of 5' untranslated sequence, either the P210 or P185 bcr-abl fusion joints, and human abl fused to Drosophila abl at a conserved NcoI site (see Figure 1).…”

Bcl-2-independent Bcr–Abl-mediated resistance to apoptosis: protection is correlated with up regulation of Bcl-xL

“…The transforming potential of this oncoprotein is related to its tyrosine kinase activity (Lugo et al, 1990;McLaughlin et al, 1989) and also to the coupling of downstream signal transduction pathways, which is provided by multiple functional domains (Afar et al, 1994;Cortez et al, 1995;Goga et al, 1995;Muller et al, 1991;Pendergast et al, 1993). Point mutations in the autophosphorylation site in the SH1 domain or in the conserved FLVRES motif within the SH2 domain impair the potential of the Bcr ± Abl molecule to transform ®broblasts (Afar et al, 1994).…”

The leukaemic oncoproteins Bcr-Abl and Tel-Abl (ETV6/Abl) have altered substrate preferences and activate similar intracellular signalling pathways

“…Among the signalling pathways which are activated by Bcr-Abl are the Ras-MAPK/Erk (Pendergast et al, 1993;Puil et al, 1994;Tauchi et al, 1998), the PI3 kinase-Akt/PKB (Skorski et al, 1997) and the JNK-c-Jun pathway (Raitano et al, 1995). Moreover, p210Bcr-Abl and p190Bcr-Abl have been shown to induce transformation of haematopoietic cells (McLaughlin et al, 1989) and to produce leukaemias in mice (Daley et al, 1990;Elefanty et al, 1990;Heisterkamp et al, 1990).…”