LAUSR

INTRODUCTION B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is the most common neoplasm in children. One of the long known recurrent rearrangements in BCP-ALL is t(1;19)(q23;p13.3)/TCF3::PBX1. However, other TCF3 gene rearrangements were also described that are associated with significant difference in ALL prognosis. METHODS The current study aimed to analyze the spectrum of TCF3 gene rearrangements in children in Russian Federation. A cohort of 203 patients with BCP-ALL was selected based on FISH screening and was studied by karyotyping, FISH, RT-PCR and high throughput sequencing. RESULTS T(1;19)(q23;p13.3)/TCF3::PBX1 is the most common aberration in TCF3-positive pediatric BCP-ALL (87.7%), with its unbalanced form prevailing. It resulted from TCF3::PBX1 exon 16-exon 3 fusion junction (86.2%) or unconventional exon 16-exon 4 junction (1.5%). Rarer events included t(12;19)(p13;p13.3)/TCF3::ZNF384 (6.4%) and t(17;19)(q21-q22;p13.3)/TCF3::HLF (1.5%). The latter translocations demonstrated high molecular heterogeneity and complex structure-four distinct transcripts were shown for TCF3::ZNF384 and each patient with TCF3::HLF had a unique transcript. These features hamper TCF3 rearrangement primary detection by molecular methods and brings FISH screening to the fore. A case of novel TCF3::TLX1 fusion in a patient with t(10;19)(q24;p13) was also discovered. Survival analysis within the national pediatric ALL treatment protocol demonstrated the severe prognosis of TCF3::HLF compared to both TCF3::PBX1 and TCF3::ZNF384. CONCLUSION So, high molecular heterogeneity of TCF3 gene rearrangement in pediatric BCP-ALL was demonstrated and a novel fusion gene TCF3::TLX1 was described.