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
Jazyk angličtina Země Spojené státy americké Médium print-electronic
Typ dokumentu časopisecké články, práce podpořená grantem
PubMed
29726059
DOI
10.1002/gcc.6
Knihovny.cz E-zdroje
- Klíčová slova
- ABL1, AIF1L, ETV6, ETV6-ABL1, acute lymphoblastic leukemia,
- MeSH
- akutní lymfatická leukemie krev genetika patologie MeSH
- chromozomální aberace MeSH
- DNA vazebné proteiny krev genetika MeSH
- fúzní onkogenní proteiny genetika MeSH
- HEK293 buňky MeSH
- hybridizace in situ fluorescenční MeSH
- karyotypizace MeSH
- lidé MeSH
- mikrofilamentové proteiny MeSH
- novorozenec MeSH
- onkogenní proteiny v-abl krev genetika MeSH
- protein ETS, translokační varianta 6 MeSH
- proteiny vázající vápník MeSH
- protoonkogenní proteiny c-ets krev genetika MeSH
- regulace genové exprese u nádorů genetika MeSH
- represorové proteiny krev genetika MeSH
- transkriptom genetika MeSH
- translokace genetická genetika MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- novorozenec MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- AIF1 protein, human MeSH Prohlížeč
- DNA vazebné proteiny MeSH
- fúzní onkogenní proteiny MeSH
- mikrofilamentové proteiny MeSH
- onkogenní proteiny v-abl MeSH
- proteiny vázající vápník MeSH
- protoonkogenní proteiny c-ets MeSH
- represorové proteiny MeSH
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.
CLIP Childhood Leukaemia Investigation Prague Prague Czech Republic
Department of Pediatrics 3rd Faculty of Medicine Charles University Prague Czech Republic
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