PML/RARα Translocation Probe Dual Fusion

The fusion gene PML/RARα is created by the t(15;17)(q22;q21) translocation found in 98% of AML M3 Acute hypergranular Promyelocytic Leukaemia and 9% of AML overall.1,2,3 The annual incidence is 1/106 and the disease may occur at any age, although often young adults are affected. The breakpoint in PML is variable between intron 3 and exon 7a, in contrast to the RARα breakpoint which remains constant in intron 2. Variant translocations include breakpoints 11q23, 5q32 and 11q13, three way translocations indicate that the critical event occurs on der(15) which always receives the distal end of chromosome 17. The cells are blocked at the promyelocytic stage of differentiation and then proliferate. The PML protein is a transcription factor, and RARα encodes a nuclear receptor. The fusion protein generated, PMLRARα, is a chimeric transcription factor that operates as a dominant negative form of RARα. A gain of function mutation allows repression of multiple genes and recruitment of DNA methyl transferases to promoters allowing prolonged suppression. PML-RARα also activates components of the Wnt signalling pathway promoting stem cell renewal. Immediate treatment is critical as intravascular coagulation causes early death in 10-40% of cases. Terminal differentiation is induced by the use of all-trans-retinoic-acid (ATRA) which reactivates the RARα gene and degrades the PMLRARα fusion. 80-90% of cases achieve complete remission. Despite the efficacy of ATRA the death rate is 15- 20% but 70% will achieve 3 year survival.2 Additional abnormalities found include trisomy 8, seen in one third of cases, del(7q) and del(9q) (Huret and Chomienne 1998).

The PML probe mix contains a probe 107kb proximal to PML, measuring 152kb, and a second probe 169kb distal to PML, measuring 107kb. Both are labelled in red. For RARα, the probes cover a 194kb region proximal to RARα, including CABC3 and a second probe (166kb) including 13kb of the distal end of RARα and extending 153kb beyond the end of the gene. Both are labelled in green.