Borrow, Julian; (1992) Molecular analysis of the t(15;17) translocation in acute promyelocytic leukaemia. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Acute promyelocytic leukaemia (APL, FAB M3) is a life-threatening haematological disorder characterized by an abundance of malignant promyelocytes in the bone marrow and blood. The cytogenetic hallmark of these promyelocytes is a recurrent translocation between the long arms of chromosomes 15 and 17, t(15;17)(q22;q11.2-12) which is seen in almost all cases. In common with other specific chromosomal changes observed in neoplasia, the translocations breakpoints are thought to pinpoint genes involved in the genesis of the disease. The aim of this PhD was to clone the t(15;17) breakpoint in APL and characterize the genes disrupted by this diagnostic translocation. The positional cloning strategy chosen to clone the APL breakpoint required the construction of a NotI linking library from chromosome 17q and the regional assignment of clones on a somatic cell hybrid mapping panel. One of the linking clones detected the translocation breakpoint as a band shift on pulsed field gel electrophoresis and was shown to span the breakpoint region on chromosome 17. Sequence analysis of cDNAs obtained from the region demonstrated that the retinoic acid receptor alpha gene (RARA), a member of the nuclear receptor superfamily, was disrupted by the translocation. The indictment of RARA at the translocation breakpoint may help explain the unique response of APL patients to differentiation therapy with the high affinity ligand of RARA, all-trans retinoic acid. Using RARA it was possible to walk over the translocation breakpoint and identify the breakpoint locus on chromosome 15, PML. Fusion messages between RARA and PML cDNAs were isolated, and two breakpoint positions were identified within PML. Both PML-RARA and RARA-PML fusion messages were isolated, indicating that both chromosome derivatives are transcriptionally active in APL. The PML-RARA message forms the basis of a diagnostic RT-PCR for APL. Variant APL translocations were also investigated.

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