RUNX1 rearrangements are common genetic abnormalities in acute leukemia. The t(7;21)(p22;q22) translocation, recently described in three cases of myeloid neoplasias, fuses the ubiquitin specific peptidase 42 gene, USP42, a member of the deubiquitinating enzyme family, to RUNX1. In this study, we characterized the semicryptic t(7;21)(p22;q22) translocation, identified by fluorescent in situ hybridization and spectral karyotyping, in a novel case of acute myeloid leukemia. Sequence analysis of the reverse transcription-polymerase chain reaction products confirmed the presence of two in-frame RUNX1-USP42 and one reciprocal in-frame USP42-RUNX1 fusion transcripts. Bioinformatic analysis of the genomic translocation breakpoints revealed microhomologies and insertion of shared nucleotides at the junctions. A topoisomerase II sequence was also detected near the break site. Additionally, we demonstrated a significant overexpression of the rearranged USP42 gene in t(7;21) positive cells using quantitative real-time PCR. Our results provide the first evidence of the possible involvement of the nonhomologous end-joining mechanism in the origin of the recurrent t(7;21) translocation. Moreover, presence of the complete catalytic USP site in the putative chimeric proteins and the upregulated expression of USP42 suggest a role of the deubiquitinating enzyme in the pathogenesis of this leukemia.
RUNX1, a key regulator of hematopoiesis, is frequently mutated or implicated in chromosomal translocations in acute leukemia. About half of RUNX1 translocations remain uncharacterized at the molecular level. We describe here one such event, a t(15;21)(q26.1;q22) translocation identified in an adult patient diagnosed with a t(9;22)(q34;q11.2)-positive acute leukemia. This previously unreported rearrangement yields a fusion of RUNX1 with the antisense strand of the SV2B gene, a new translocation partner of RUNX1, resulting in the expression of out-of-frame mRNA chimeric transcripts and the production of putative truncated RUNX1 isoforms. The t(15;21) translocation also dissociates the P1 promoter of RUNX1 from its open reading frame, reducing RUNX1 expression levels in the patient's leukemic cells. Our data suggest that RUNX1 haploinsufficiency collaborates with the BCR-ABL1 oncogene in this leukemia. The description of this atypical gene fusion is an important addition to the characterization of the pathogenomic mechanisms leading to RUNX1 structural and functional alterations. Furthermore, our data strongly suggests that inadequate dosage of this gene plays an essential role in leukemogenesis.
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