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Unlike more common fusion genes generated via simple reciprocal chromosomal translocations, formation of the <jats:italic>ETV6\u2010ABL1<\/jats:italic> 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 <jats:italic>ETV6\u2010ABL1<\/jats:italic> and 2 novel fusion genes: <jats:italic>AIF1L\u2010ETV6<\/jats:italic> and <jats:italic>ABL1\u2010AIF1L<\/jats:italic>. We demonstrate the prenatal origin of this complex chromosomal rearrangement, which apparently initiated the leukemogenic process, by successful backtracking of the <jats:italic>ETV6\u2010ABL1<\/jats:italic> fusion into the patient's archived neonatal blood. We cloned coding sequences of <jats:italic>AIF1L\u2010ETV6<\/jats:italic> and <jats:italic>ABL1\u2010AIF1L<\/jats:italic> in\u2010frame fusion transcripts from the patient's leukemic blasts and we show that the chimeric protein containing the DNA binding domain of <jats:italic>ETV6<\/jats:italic> is expressed from the <jats:italic>AIF1L\u2010ETV6<\/jats:italic> 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\u2010like gene expression signature and loss of the <jats:italic>IKZF1<\/jats:italic> and <jats:italic>CDKN2A\/B<\/jats:italic> genes, the typical genetic lesions accompanying <jats:italic>ETV6\u2010ABL1<\/jats:italic>\u2010positive ALL. The prenatal origin of the rearrangement confirms that <jats:italic>ETV6\u2010ABL1<\/jats:italic> is not sufficient to cause overt leukemia, even when combined with the 2 novel fusions. We did not find the <jats:italic>AIF1L\u2010ETV6<\/jats:italic> and <jats:italic>ABL1\u2010AIF1L<\/jats:italic> fusions in other <jats:italic>ETV6\u2010ABL1<\/jats:italic>\u2010positive ALL. Nevertheless, functional studies would be needed to establish the biological role of <jats:italic>AIF1L\u2010ETV6<\/jats:italic> and <jats:italic>ABL1\u2010AIF1L<\/jats:italic> and to determine whether they contribute to leukemogenesis and\/or to the final leukemia phenotype.<\/jats:p>","DOI":"10.1002\/gcc.6","type":"journal-article","created":{"date-parts":[[2018,5,4]],"date-time":"2018-05-04T09:01:13Z","timestamp":1525424473000},"page":"471-477","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Two novel fusion genes, <i>AIF1L\u2010ETV6<\/i> and <i>ABL1\u2010AIF1L<\/i>, result together with <i>ETV6\u2010ABL1<\/i> from a single chromosomal rearrangement in acute lymphoblastic leukemia with prenatal origin"],"prefix":"10.1002","volume":"57","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1487-537X","authenticated-orcid":false,"given":"Julius","family":"Lukes Jr","sequence":"first","affiliation":[{"name":"CLIP 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Haematology and Oncology Second Faculty of Medicine, Charles University Prague Czech Republic"},{"name":"University Hospital Motol Prague Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felix","family":"Votava","sequence":"additional","affiliation":[{"name":"Department of Pediatrics 3rd Faculty of Medicine, Charles University Prague Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Zuna","sequence":"additional","affiliation":[{"name":"CLIP \u2010 Childhood Leukaemia Investigation Prague Prague Czech Republic"},{"name":"Department of Paediatric Haematology and Oncology Second Faculty of Medicine, Charles University Prague Czech Republic"},{"name":"University Hospital Motol Prague Czech 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