Expression of a Distinctive BCR-ABL Oncogene in Ph ¹ -Positive Acute Lymphocytic Leukemia (ALL)

Abstract

The Philadelphia chromosome (Ph1) is a translocation between chromosomes 9 and 22 that is found in chronic myelogenous leukemia (CML) and a subset of acute lymphocytic leukemia patients (ALL). In CML, this results in the expression of a chimeric 8.5-kilobase BCR-ABL transcript that encodes the P210BCR-ABL tyrosine kinase. The Ph1 chromosome in ALL expresses a distinct ABL-derived 7-kilobase messenger RNA that encodes the P185ALL-ABL protein. Since the expression of different oncogene products may play a role in the distinctive presentation of Ph1-positive ALL versus CML, it is necessary to understand the molecular basis for the expression of P185ALL-ABL. Both P210BCR-ABL and P185ALL-ABL are recognized by an antiserum directed to BCR determinants in the amino-terminal region of both proteins. Antisera to BCR determinants proximal to the BCR-ABL junction in CML immunoprecipitated P210BCR-ABL but not P185ALL-ABL. Nucleotide sequence analysis of complementary DNA clones made from RNA from the Ph1-positive ALL SUP-B15 cell line, and S1 nuclease protection analysis confirmed the presence of BCR-ABL chimeric transcripts in Ph1-positive ALL cells. In Ph1-positive ALL, ABL sequences were joined to BCR sequences approximately 1.5 kilobases 5' of the CML junction. P185ALL-ABL represents the product of a BCR-ABL fusion gene in Ph1-positive ALL that is distinct from the BCR-ABL fusion gene of CML.

Fusion tyrosine kinases: a result and cause of genomic instability

“…It is present in chronic myelogenous leukemia (CML) and a cohort of acute lymphoblastic leukemia (ALL) patients (Shtivelman et al, 1986;Clark et al, 1988;Epner and Koeffler, 1990). BCR/FGFR1 is produced by the fusion between BCR exon 4 and FGFR1 exon 9 and was reported in a spectrum of myeloproliferative disorders that include CML-like disease (Demiroglu et al, 2001;Fioretos et al, 2001).…”

Split-signal FISH for detection of chromosome aberrations in acute lymphoblastic leukemia

“…97,105,106 The resulting e1-a2 fusion transcript encodes the p190 BCR-ABL fusion protein. Although the p190 BCR-ABL fusion protein is mainly found in ALL, it is linked to 3% of atypical CML cases.…”

The in vitro activity of the tyrosine kinase inhibitor STI571 in BCR–ABL positive chronic myeloid leukaemia cells: synergistic interactions with anti-leukaemic agents

“…The bcr -abl gene created by this inter-chromosomal exchange encodes one of two fusion proteins, p185 and p210, that display elevated and dysregulated TK activity, and forms the fundamental mechanism underlying CML positive cells. The p210 form of BCR -ABL is seen in 95% of all patients with CML and up to 20% of adult patients with acute lymphocytic leukaemia (ALL) (Bartram et al, 1983;Shtivelman et al, 1985), whereas the p185 form is seen in 5 -10% of de novo ALL (Hermans et al, 1987;Clark et al, 1988). Currently, allogeneic bone marrow transplantation is the only proven curative therapy for CML, and the cure rate for approximately one-third of CML patients that are eligible is 70 -90% (Kantarjian et al, 1993;Goldman, 1994).…”