Two novel fusion genes, AIF1L‐ETV6 and ABL1‐AIF1L, result together with ETV6‐ABL1 from a single chromosomal rearrangement in acute lymphoblastic leukemia with prenatal origin

Abstract Fusion genes resulting from chromosomal rearrangements represent a hallmark of childhood acute lymphoblastic leukemia (ALL). Unlike more common fusion genes generated via simple reciprocal chromosomal translocations, formation of the ETV6‐ABL1 fusion gene requires 3 DNA breaks and usually results from an interchromosomal insertion. We report a child with ALL in which a single interchromosomal insertion led to the formation of ETV6‐ABL1 and 2 novel fusion genes: AIF1L‐ETV6 and ABL1‐AIF1L . We demonstrate the prenatal origin of this complex chromosomal rearrangement, which apparently initiated the leukemogenic process, by successful backtracking of the ETV6‐ABL1 fusion into the patient's archived neonatal blood. We cloned coding sequences of AIF1L‐ETV6 and ABL1‐AIF1L in‐frame fusion transcripts from the patient's leukemic blasts and we show that the chimeric protein containing the DNA binding domain of ETV6 is expressed from the AIF1L‐ETV6 transcript and localized in both the cytoplasm and nucleus of transfected HEK293T cells. Transcriptomic and genomic profiling of the diagnostic bone marrow sample revealed Ph‐like gene expression signature and loss of the IKZF1 and CDKN2A/B genes, the typical genetic lesions accompanying ETV6‐ABL1 ‐positive ALL. The prenatal origin of the rearrangement confirms that ETV6‐ABL1 is not sufficient to cause overt leukemia, even when combined with the 2 novel fusions. We did not find the AIF1L‐ETV6 and ABL1‐AIF1L fusions in other ETV6‐ABL1 ‐positive ALL. Nevertheless, functional studies would be needed to establish the biological role of AIF1L‐ETV6 and ABL1‐AIF1L and to determine whether they contribute to leukemogenesis and/or to the final leukemia phenotype.