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.

Genomic landscape of pediatric B-other acute lymphoblastic leukemia in a consecutive European cohort

“…The ETV6-ABL1 fusion was found in a BCR-ABL1 -like ALL patient and was accompanied by another two in-frame fusions resulting from a single chromosomal rearrangement that we recently characterized in a separate report. 43…”

New biological and genetic classification and therapeutically relevant categories in childhood B-cell precursor acute lymphoblastic leukemia

“…It should be discussed carefully whether it is justified to use TKIs in all children with any targetable kinase-activating aberration, whether they should be used only in children harboring a lesion unambiguously associated with unfavorable outcome (similar to BCR–ABL1 fusion), or whether the TKIs should be reserved for patients with worse early response to treatment or with resistant disease, where the potential benefits most likely outweigh an increase of treatment toxicity 77 . Moreover, it is important to consider that while some of the kinase and cytokine-receptor gene alterations are supposed to represent founding lesions present in all leukemic cells and essential for their survival 10 , 78 – 80 , some aberrations may be either founding or secondary lesions (for example, CRLF2 r) and others are typically secondary subclonal lesions (for example, JAK / RAS gene mutations), possibly without a resistance- or relapse-driving role, thus probably representing less-suitable therapeutic targets 46 , 81 .…”

Complex Genomic Rearrangements Involving ETV6::ABL1 Gene Fusion in an Individual with Myeloid Neoplasm

“…Information regarding the genomic rearrangement, content, and breakpoints involving in the fusion at the molecular level is lacking. To our knowledge, four mechanisms regarding the formation of in-frame ETV6::ABL1 gene fusion have been reported, including the insertion of 5 ETV6 into ABL1 [11][12][13][14], the insertion of 3 ABL1 into ETV6 [15][16][17][18], the inversion of 9q (reversing ABL1) in combination with a t(9;12) translocation [19,20], and ETV6 insertion and translocation involving multiple chromosomes [21]. Except for chromosomal findings, however, all these mechanisms lacked molecular evidence at the DNA level.…”