BCR/ABL Translocation Dual Fusion LPH038 - Detail

The presence of the Philadelphia chromosome (Ph') has important diagnostic and prognostic implications in a number of Haematological disorders. The abnormality is characteristic of Chronic Myeloid Leukaemia (CML), found in around 90% of cases but represents a significant abnormality in 30% of adult and 2 to 10% of childhood¹ Acute Lymphoblastic Leukaemia (ALL) cases^2,3,4. This rearrangement is also seen in rare cases of acute myelogenous leukemia (AML) ⁵. As a result of the Philadelphia translocation, t(9;22)(q34;q11), the ABL (Abelson) proto-oncogene and the BCR (Breakpoint Cluster Region) gene fuse, giving rise to the BCR/ABL hybrid or 'fusion' gene. The breakpoints in the CML translocation have been located in sub-bands 22q11.21 and 9q34.1⁶. The translocation between chromosomes 9 and 22 can be accompanied by loss of proximal sequence (ASS/ABL) and distal 22q found in ALL and rare cases of AML. The deletion of 9q encompassing the ASS gene is associated with poor prognosis and the time to disease progression on imatinib treatment is shorter. Therefore the establishment of the atypical patterns in the BCR/ABL translocation may have clinical diagnostic and prognostic implications⁷. In BCR there are two breakpoint regions, m-BCR and M-BCR. In CML most translocations involve the Major Breakpoint Cluster Region (M-BCR) located approximately between exons 12 to 16. In ALL, breaks mostly fall in the Minor Breakpoint Cluster Region (m-BCR) located between exons 1 and 2 though the resulting translocation is cytogenetically identical to that of CML. These alternative breakpoints join different exon sets of BCR to a common subset of the exons of the ABL resulting in 2 alternative chimeric oncogene products, p210 (BCR-ABL) and p185 (BCRABL). Both of these fusion proteins possess enhanced tyrosine kinase activity through the activation of ABL tyrosine kinase activity by the direct physical binding of sequences within the first exon of BCR. It is thought that this kinase activity is necessary for the oncogenic potential of the chimeric oncogene. In ALL, the rearrangement is associated with an extremely poor outcome with an event-free survival (EFS) of 15% or less at 5 years in adult and childhood patients treated with chemotherapy alone^8,9. There are no reports of long-term survivors¹⁰. Allogeneic bone marrow transplantation is the only curative therapy for these patients. Children with this rearrangement are treated on a high-risk protocol and adults are recommended for immediate bone marrow transplantation. Philadelphia (Ph) chromosomepositive acute myeloid leukaemia (AML) is characterized by its resistance to conventional standard chemotherapy and poor prognosis so accurate and rapid identification of this chromosomal abnormality is vital. In a small number of cases of ALL, the translocation does not result in a cytogenetically visible Philadelphia chromosome. In these cases, FISH is essential for highlighting the fusion gene¹¹.

Reference:/Bibliographie/Literatur/Bibliografia

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