PML/RARα(RARA) Translocation, Dual Fusion
- PML, 15q24.1, Red
- RARα, 17q21.1-q21.2, Green
The PML probe mix, labelled in red, consists of a 151kb probe centromeric to the PML gene and a 174kb probe telomeric to the PML gene. The RARα probe mix, labelled in green, consists of a 167kb probe centromeric to the RARα (RARA) gene, including the CASC3 gene, and a 164kb probe, including the telomeric end of the RARα gene as well as the TOP2A and IGFBP4 genes.
The fusion gene PML/RARA is created by the t(15;17)(q24.1;q21.2) translocation, found in 98% of AML M3 acute hypergranular promyelocytic leukaemia and 9% of AML overall1,2,3.
Breakpoints in the PML gene vary between intron 3 and exon 7a, which is in contrast to the RARA breakpoint, which remains constant in intron 2. Variant translocations include partner breakpoints in 11q23, 5q32 and 11q13. The presence of three-way translocations indicate that the critical event occurs on the der(15), which always receives the distal end of chromosome 17.
The PML protein is a transcription factor and RARA encodes a nuclear receptor. The fusion protein generated, PML-RARA, is a chimaeric transcription factor that operates as a dominant negative form of RARA and results in cells that are blocked at the promyelocytic stage of differentiation and then proliferate. Gain of function mutation allows repression of multiple genes and recruitment of DNA methyltransferases to promoters, allowing prolonged suppression. PML-RARA also activates components of the WNT signalling pathway, promoting stem cell renewal.
Immediate treatment of PML/RARA positive patients is critical as intravascular coagulation causes early death in 10-40% of cases2. Terminal differentiation is induced by the use of all-trans-retinoic-acid (ATRA), which reactivates the RARA gene and degrades the PML-RARA fusion product and 80-90% of treated patients achieve complete remission1,2,4. Despite the efficacy of ATRA, the death rate remains around 15-20%, but 70% of patients will achieve 3 year survival2. Additional abnormalities found with PML/RARA translocations include trisomy 8, seen in one third of cases, del(7q) and del(9q)2.
I first came across Cytocell FISH probes in a previous lab I worked in and I was struck by the quality of the products. Since this time, I have been recommending and introducing Cytocell probes across all application areas — now they are the primary FISH probes used in our lab. They have an excellent range of products and their ready-to-use reagent format saves considerable time. As a matter of fact, at a recent conference there was a discussion about the lack of commercial probes for a particular disorder and I was happy to point the participants in the direction of the Cytocell catalogue, which contains the exact probes required. Elizabeth Benner, Medical Technologist at the University of Arizona Health Network
1. Licht, Sternberg, The Molecular Pathway of AML. ASH Education Book 2005;137-42
2. Huret and Chomienne. t(15;17)(q24;q21). Atlas Genet Cytogenet Oncol Haematol 1998;2(3):329-34
3. Heim and Mitelman, Willey-Liss, Inc. 1995
4. Greaves, BMJ 2002;324(7332):283-7
- Area of Interest*
This product is intended to be used on Carnoy’s solution (3:1 methanol/acetic acid) fixed haematological samples.
*Disease information supported by the literature and is not a reflection of the intended purpose of this product.