Detection of a cryptic NUP214/ABL1 gene fusion by mate-pair sequencing (MPseq) in a newly diagnosed case of pediatric T-lymphoblastic leukemia

Abstract

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematopoietic neoplasm involving the bone marrow and blood that accounts for ∼15% of childhood and 25% of adult ALL. Whereas multiple, recurrent genetic abnormalities have been described in T-ALL, their clinical significance is unclear or controversial. Importantly, ABL1 rearrangements, most commonly described in BCR/ABL1 -positive B-ALL and BCR-ABL1 -like B-ALL, have been observed in T-ALL and may respond to tyrosine kinase inhibitor (TKI) therapy. We describe a newly diagnosed case of pediatric T-ALL with a fluorescence in situ hybridization abnormality suggesting a partial ABL1 deletion by a BCR / ABL1 dual-color dual-fusion probe but that demonstrated a normal result using an ABL1 break-apart probe. Mate-pair sequencing (MPseq), a next-generation sequencing (NGS)-based technology utilized to detect copy number and structural abnormalities with high resolution and precision throughout the genome, was performed and revealed a NUP214 / ABL1 gene fusion that has been demonstrated to be sensitive to TKI therapy. This case demonstrates the power of MPseq to resolve chromosomal abnormalities unappreciable by traditional cytogenetic methodologies and highlights the clinical value of this novel NGS-based technology.

Case Report: The First Report of NUP214-ABL1 Fusion Gene in Acute Myeloid Leukemia Patient Detected by Next-Generation Sequencing

“…In this report, the patient received conventional AML-type chemotherapy, and he achieved a CR at the end of induction. Additionally, similar to our case, some patients with NUP214-ABL1 fusion are treated by conventional chemotherapy without using TKIs and achieve a CR at the end of induction (9,15). However, if this patient experiences relapse, we may consider adding TKIs, as previous studies suggested that NUP214-ABL1-positive patients could benefit from TKIs post relapse (12,13).…”

“…In this case, we revealed the presence of the NUP214-ABL1 fusion through NGS and confirmed it by RT-PCR. Therefore, RT-PCR and some high-resolution sequencing, such as NGS, appear to be a very useful method to identify NUP214-ABL1 fusions ( 10 , 15 ). In addition, our case did not have extrachromosomal ABL1 amplification, which is similar to the results of previous studies detected by FISH ( 2 , 14 ).…”

Mate pair sequencing outperforms fluorescence in situ hybridization in the genomic characterization of multiple myeloma

“…Some laboratories have incorporated the use of chromosomal microarray analysis in the detection of CNAs such as hyperdiploidy, 17p deletions and 1q gains, however microarray studies are unable to identify balanced structural rearrangements necessitating the use of other methodologies in the detection of IGH rearrangements 15 . It has also become increasingly apparent that some FISH probes, such as those targeting MYC rearrangements, display evidence of false negative results 18–22 . In addition, FISH panels for PCNs are variable between individual laboratories, provide a limited view of the whole genome and may not always reflect genomic complexity.…”

“…They allow for the interrogation of only the regions for which FISH probes are available and multiple FISH probes are needed in order to be comprehensive, with each probe requiring a resource-consuming validation. More importantly, FISH has the potential to miss cryptic abnormalities, including rearrangements that result in a position effect due to juxtaposition of enhancers near oncogenes 18–22 . Since many translocations identified in MM involve a position effect (i.e., IGH and MYC ) with heterogeneous breakpoints 10,23,24 and some CNAs may be cryptic, we hypothesize that some clinical FISH probes used in the characterization of PCNs have a high rate of false negative FISH results.…”

Detection of NUP214-ABL1 translocation using BCR-ABL1 dual color FISH probes in T-cell acute lymphoblastic leukemia–;an illustrative report and review of literature

“…Although BCR-ABL1-positive T-ALL is rare, the frequency of its detection has increased, with approximately 30 cases reported in the literature and pediatric cases accounting for more than 40% of the total cases. In most reported cases, the prognosis was poor with a median survival of only 7 months (range, 0.1-60 mo), and nearly 50% of the patients died by the time of the last follow-up [8][9][10][11][12][13][14][15].…”