UNEXPECTED CONCOMITANCE OF ETV6-RUNX1 AND BCR-ABL1P210 IN A CHILD WITH B-CELL PRECURSOR ACUTE LYMPHOBLASTIC LEUKEMIA

Abstract

ETV6-RUNX1 and BCR-ABL1 are recurrent primary events in pediatric B-cell precursor acute lymphoblastic leukemia (B-ALL), being the former the most common one. Elegant studies have shown that these are founder events, but additional genetic events are needed for leukemia development. Nonetheless, these common primary alterations are typically mutually exclusive. The presence of both ETV6-RUNX1 and BCR-ABL1 is a very rare event which has been previously reported in only two B-ALL cases, being one pediatric and one adult patient. Herein, we report a rare pediatric B-ALL case with simultaneous occurrence of ETV6-RUNX1 and BCR-ABL1 . A 5-year-old boy was admitted to Hospital Federal da Lagoa, Rio de Janeiro, Brazil. At clinical investigation, he presented hepatosplenomegaly, a white blood cell count of 0.7×10 9 /L, 94% of blasts, Hb of 6.5 g/L, and platelet count of 16×10 9 /L. The patient was treated according to the AIEOP-BFM protocol. He presented a poor prednisone response (at day 8; >1000 circulating lymphoblasts), the minimal residual disease at day 33 was negative (0.08%), and he was considered in complete remission. Four months after the diagnosis, the child is alive with negative levels of residual disease. The immunophenotyping was characterized by nTdT (low), CD10, CD13, CD19, CD21, CD22, CD24, CD33, CD34, CD38 and CD45, cCD66c, cCD79, CD81, CD123, and CD58 positive cells in 94.1% of lymphoblast cells and a diploid profile (DNA index of 1.09). ETV6-RUNX1 and BCR-ABL1 p210 were identified by reverse transcriptase PCR (RT-PCR). The presence of both rearrangements was confirmed by sanger sequencing. Moreover, additional copy number alterations (CNA) were evaluated by multiplex ligation-dependent probe amplification (MLPA) using SALSA MLPA P335-C1. Deletions affecting IKZF1 (exons 2 and 3), CDKN2A (exons 2 and 5), CDKN2B (exon 2), PAX5 (exon 1), and ETV6 (exons 2, 3, 5 and 8) were detected. In consonance with previous studies, these CNAs are the most frequently secondary events found in patients with ETV6-RUNX1 . Of note, IKZF1 deletions are enriched in patients with BCR-ABL1 . Due to the lack of material for FISH analysis, the clonality of both biomarkers could not be verified. However, we observed a low load of BCR-ABL1 p210 transcript in comparison with the endogenous gene, suggesting that this gene fusion could be present in subclones. In conclusion, to the best of our knowledge, this is the second pediatric case identified with ETV6-RUNX1 and BCR-ABL1 gene rearrangement in concomitance, but is the first case reported with the p210 transcript, which is extremely rare in B-ALL. Previous studies have shown that the additional genetic events found can impact the usually favorable prognosis of ETV6-RUNX1 – positive B-ALL. The clinical significance for these rare patients with both rearrangements remains unclear due to the small number of reported cases to date. Therefore, it is very important to describe more cases which will ultimately enable future studies with larger series and clarify this enigmatic subgroup.