• Something wrong with this record ?

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

J. Lukes, E. Potuckova, L. Sramkova, J. Stary, J. Starkova, J. Trka, F. Votava, J. Zuna, M. Zaliova,

. 2018 ; 57 (9) : 471-477. [pub] 20180730

Language English Country United States

Document type Journal Article, Research Support, Non-U.S. Gov't

Persistent link   https://www.medvik.cz/link/bmc19000766

Grant support
NV15-30626A MZ0 CEP Register

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.

References provided by Crossref.org

000      
00000naa a2200000 a 4500
001      
bmc19000766
003      
CZ-PrNML
005      
20190121095010.0
007      
ta
008      
190107s2018 xxu f 000 0|eng||
009      
AR
024    7_
$a 10.1002/gcc.6 $2 doi
035    __
$a (PubMed)29726059
040    __
$a ABA008 $b cze $d ABA008 $e AACR2
041    0_
$a eng
044    __
$a xxu
100    1_
$a Lukes, Julius $u CLIP - Childhood Leukaemia Investigation Prague, Prague, Czech Republic. Department of Paediatric Haematology and Oncology, Second Faculty of Medicine, Charles University, Prague, Czech Republic.
245    10
$a 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 / $c J. Lukes, E. Potuckova, L. Sramkova, J. Stary, J. Starkova, J. Trka, F. Votava, J. Zuna, M. Zaliova,
520    9_
$a 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.
650    _2
$a chromozomální aberace $7 D002869
650    _2
$a DNA vazebné proteiny $x krev $x genetika $7 D004268
650    _2
$a ženské pohlaví $7 D005260
650    _2
$a regulace genové exprese u nádorů $x genetika $7 D015972
650    _2
$a HEK293 buňky $7 D057809
650    _2
$a lidé $7 D006801
650    _2
$a hybridizace in situ fluorescenční $7 D017404
650    _2
$a novorozenec $7 D007231
650    _2
$a karyotypizace $7 D007621
650    _2
$a mužské pohlaví $7 D008297
650    _2
$a onkogenní proteiny v-abl $x krev $x genetika $7 D016374
650    _2
$a fúzní onkogenní proteiny $x genetika $7 D015514
650    _2
$a akutní lymfatická leukemie $x krev $x genetika $x patologie $7 D054198
650    _2
$a protoonkogenní proteiny c-ets $x krev $x genetika $7 D050783
650    _2
$a represorové proteiny $x krev $x genetika $7 D012097
650    _2
$a transkriptom $x genetika $7 D059467
650    _2
$a translokace genetická $x genetika $7 D014178
655    _2
$a časopisecké články $7 D016428
655    _2
$a práce podpořená grantem $7 D013485
700    1_
$a Potuckova, Eliska $u CLIP - Childhood Leukaemia Investigation Prague, Prague, Czech Republic. Department of Paediatric Haematology and Oncology, Second Faculty of Medicine, Charles University, Prague, Czech Republic.
700    1_
$a Sramkova, Lucie $u CLIP - Childhood Leukaemia Investigation Prague, Prague, Czech Republic. Department of Paediatric Haematology and Oncology, Second Faculty of Medicine, Charles University, Prague, Czech Republic. University Hospital Motol, Prague, Czech Republic.
700    1_
$a Stary, Jan $u Department of Paediatric Haematology and Oncology, Second Faculty of Medicine, Charles University, Prague, Czech Republic. University Hospital Motol, Prague, Czech Republic.
700    1_
$a Starkova, Julia $u CLIP - Childhood Leukaemia Investigation Prague, Prague, Czech Republic. Department of Paediatric Haematology and Oncology, Second Faculty of Medicine, Charles University, Prague, Czech Republic.
700    1_
$a Trka, Jan $u CLIP - Childhood Leukaemia Investigation Prague, Prague, Czech Republic. Department of Paediatric Haematology and Oncology, Second Faculty of Medicine, Charles University, Prague, Czech Republic. University Hospital Motol, Prague, Czech Republic.
700    1_
$a Votava, Felix $u Department of Pediatrics, 3rd Faculty of Medicine, Charles University, Prague, Czech Republic.
700    1_
$a Zuna, Jan $u CLIP - Childhood Leukaemia Investigation Prague, Prague, Czech Republic. Department of Paediatric Haematology and Oncology, Second Faculty of Medicine, Charles University, Prague, Czech Republic. University Hospital Motol, Prague, Czech Republic.
700    1_
$a Zaliova, Marketa $u CLIP - Childhood Leukaemia Investigation Prague, Prague, Czech Republic. Department of Paediatric Haematology and Oncology, Second Faculty of Medicine, Charles University, Prague, Czech Republic. University Hospital Motol, Prague, Czech Republic.
773    0_
$w MED00001898 $t Genes, chromosomes & cancer $x 1098-2264 $g Roč. 57, č. 9 (2018), s. 471-477
856    41
$u https://pubmed.ncbi.nlm.nih.gov/29726059 $y Pubmed
910    __
$a ABA008 $b sig $c sign $y a $z 0
990    __
$a 20190107 $b ABA008
991    __
$a 20190121095228 $b ABA008
999    __
$a ok $b bmc $g 1363916 $s 1038889
BAS    __
$a 3
BAS    __
$a PreBMC
BMC    __
$a 2018 $b 57 $c 9 $d 471-477 $e 20180730 $i 1098-2264 $m Genes, chromosomes & cancer $n Genes Chromosom Cancer $x MED00001898
GRA    __
$a NV15-30626A $p MZ0
LZP    __
$a Pubmed-20190107

Find record

Citation metrics

Archiving options