A Paediatric Acute Promyelocytic Leukaemia Patient Harbouring a Cryptic <b><i>PML-RARA</i></b> Insertion due to a Complex Structural Chromosome 17 Rearrangement

Abstract

Acute promyelocytic leukaemia with PML-RARA fusion is usually associated with the t(15;17)(q24.1;q21.1) translocation but may also arise from complex or cryptic rearrangements. The fusion usually resides on chromosome 15 but occasionally on others. We describe a cryptic PML-RARA fusion within a novel chromosome 17 rearrangement. We performed interphase fluorescence in situ hybridisation (FISH) using a dual-fusion PML-RARA probe, followed by reverse transcriptase-polymerase chain reaction (RT-PCR) for PML-RARA, karyotyping, and metaphase FISH using RARA break-apart, locus-specific, and subtelomere probes for chromosome 17. An 850K SNP microarray was also employed. Interphase and metaphase FISH showed atypical results involving a single PML-RARA fusion, no second fusion, but instead separate diminished PML and RARA signals. RT-PCR confirmed PML-RARA fusion; however, karyotyping detected only an altered chromosome 17. Metaphase FISH showed the single fusion and diminished 5′ RARA signals located unexpectedly in the subtelomeric short-arm and long-arm regions of the rearranged chromosome 17, respectively. SNP microarray revealed no copy number abnormality. This paediatric patient with PML-RARA fusion reflects a cryptic insertion that resides within a complex and novel chromosome 17 rearrangement. This rearrangement likely arose via 7 chromosome breaks with the insertion occurring first followed by sequential paracentric and then pericentric inversions.

The Alteration of Subtelomeric DNA Methylation in Aging-Related Diseases

“…It reveals the diversity behavior of the p- and q-chromosomal arm signals. Recent FISH-based studies have shown that the reduced 5′RARA signal and the single PML-RARA fusion are located in the subterminal q-arm and p-arm regions of the rearranged chromosome 17, respectively (El-Hajj Ghaoui et al, 2017). Whether in a neoplastic disease or a non-cancerous disease, disease progression depends on the quantification and quality of the signal, and these signals differ between the p- and q-arms of each chromosome.…”

“…In addition, Wu et al (2010) found that 16 patients with growth stunting or mental retardation had several deletions at 14 different subtelomeric regions (1p, 2p, 4p, 6p, 7p, 7q, 8p, 9p, 10p, 11q, 14q, 15q, 16p, and 22q) and repeats at seven subtelomeric regions (3q, 4p, 6q, 7p, 8p, 12p and 22q). What’s more, subtelomeric rearrangements are also the major cause of idiopathic mental retardation, growth stunting or retardation, and malignant blood system diseases (Ravnan et al, 2006; Tos et al, 2013; El-Hajj Ghaoui et al, 2017).…”

Acute promyelocytic leukemia with a cryptic insertion of RARA into TBL1XR1

“…The upstream part was inserted into chromosome X, whereas the downstream part was inserted into the TBL1XR1 locus. [6][7][8][9][10] Welch et al 11 demonstrated that WGS is useful for detection of PML-RARA in masked cases. The transcript of the chimeric gene, TBL1XR1-RARA, was confirmed as an inframe fusion by RT-PCR, which was identical to that of the previously reported cases ( Figure 2B).…”

“…The same situation has been reported in cases with PML-RARA-positive APL. [6][7][8][9][10] Welch et al 11 demonstrated that WGS is useful for detection of PML-RARA in masked cases.…”