Abstract
The TCF3/PBX1 gene fusion is a recurrent genetic abnormality in pediatric B-lymphoblastic leukemia/lymphoma (B-ALL/LBL). While dual-color, dual-fusion fluorescence in situ hybridization (D-FISH) probes can detect TCF3/PBX1 fusions, further characterization of atypical TCF3 FISH patterns as indicated by additional or diminished TCF3 signals is currently limited. Herein we describe the use of a next-generation sequencing assay, mate-pair sequencing (MPseq), to characterize typical and cryptic TCF3/PBX1 fusions and to identify TCF3 translocation partners based on results obtained from our laboratory-developed TCF3/PBX1 D-FISH probe set. MPseq was performed on 21 cases of pediatric B-ALL/LBL with either TCF3/PBX1 fusion, or no TCF3/PBX1 fusion but with additional or diminished TCF3 signals obtained by our PBX1/TCF3 D-FISH probe set. In addition, MPseq was performed on one pediatric B-ALL/LBL case with an apparently normal karyotype and abnormal TCF3 break-apart probe results. Of 22 specimens successfully evaluated by MPseq, 13 cases (59%) demonstrated TCF3/PBX1 fusion, including three cases with previously undescribed insertional rearrangements. The remaining nine cases (41%) harbored various TCF3 partners, including six cases with TCF3/ZNF384, and one case each with TCF3/HLF, TCF3/FLI1 and TCF3/TEF. Our results illustrate the power of MPseq to characterize TCF3 rearrangements with increased precision and accuracy over traditional cytogenetic methodologies.
Highlights
Introduction Rearrangements involving theTCF3 gene region (19p13.3) are common in both pediatric and adult B-lymphoblastic leukemia/lymphoma (B-ALL/LBL) and account for ~6% of newly diagnosed cases1–4
To further characterize TCF3/PBX1 fusions associated with discordant chromosome results and the TCF3 rearrangements with additional or diminished TCF3 signals obtained by our TCF3/ PBX1 dual-fusion fluorescence in situ hybridization (D-fluorescence in situ hybridization (FISH)) probe set, we utilized a next-generation sequencing (NGS) strategy, mate-pair sequencing (MPseq)
The MPseq results explained serial metaphase FISH, which had documented TCF3/PBX1 fusion located on a “normal” copy of chromosome 1q in each case, suggesting a cryptic insertional rearrangement
Summary
TCF3 (previously known as E2A) gene region (19p13.3) are common in both pediatric and adult B-lymphoblastic leukemia/lymphoma (B-ALL/LBL) and account for ~6% of newly diagnosed cases. The PBX1 gene (1q23) is the most common translocation partner for TCF3, resulting in TCF3/PBX1 gene fusion, and is currently classified in the WHO as a recurrent genetic abnormality in B-ALL/LBL4. Fusion of TCF3/PBX1 is usually generated from a reciprocal t(1;19) (q23;p13.3) and results in a 5′TCF3/3′PBX1 fusion gene located on the der(19)t(1;19) chromosome. Rowsey et al Blood Cancer Journal (2019)9:81 partners have been described, most commonly ZNF384 (12p13) and HLF (17q21). Since highly variable prognoses are associated with the various TCF3 translocation partners (TCF3/HLF fusion has an extremely poor prognosis in contrast to the favorable/standard risk for TCF3/ PBX1 fusion), the characterization of TCF3 partners is essential
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