title: Characterization of leukemias with ETV6-ABL1 fusion.
abstract: To characterize the incidence, clinical features and genetics of ETV6-ABL1 leukemias, representing targetable kinase-activating lesions, we analyzed 44 new and published cases of ETV6-ABL1-positive hematologic malignancies [22 cases of acute lymphoblastic leukemia (13 children, 9 adults) and 22 myeloid malignancies (18 myeloproliferative neoplasms, 4 acute myeloid leukemias)]. The presence of the ETV6-ABL1 fusion was ascertained by cytogenetics, fluorescence in-situ hybridization, reverse transcriptase-polymerase chain reaction and RNA sequencing. Genomic and gene expression profiling was performed by single nucleotide polymorphism and expression arrays. Systematic screening of more than 4,500 cases revealed that in acute lymphoblastic leukemia ETV6-ABL1 is rare in childhood (0.17% cases) and slightly more common in adults (0.38%). There is no systematic screening of myeloproliferative neoplasms; however, the number of ETV6-ABL1-positive cases and the relative incidence of acute lymphoblastic leukemia and myeloproliferative neoplasms suggest that in adulthood ETV6-ABL1 is more common in BCR-ABL1-negative chronic myeloid leukemia-like myeloproliferations than in acute lymphoblastic leukemia. The genomic profile of ETV6-ABL1 acute lymphoblastic leukemia resembled that of BCR-ABL1 and BCR-ABL1-like cases with 80% of patients having concurrent CDKN2A/B and IKZF1 deletions. In the gene expression profiling all the ETV6-ABL1-positive samples clustered in close vicinity to BCR-ABL1 cases. All but one of the cases of ETV6-ABL1 acute lymphoblastic leukemia were classified as BCR-ABL1-like by a standardized assay. Over 60% of patients died, irrespectively of the disease or age subgroup examined. In conclusion, ETV6-ABL1 fusion occurs in both lymphoid and myeloid leukemias; the genomic profile and clinical behavior resemble BCR-ABL1-positive malignancies, including the unfavorable prognosis, particularly of acute leukemias. The poor outcome suggests that treatment with tyrosine kinase inhibitors should be considered for patients with this fusion.
authors.affiliation: CLIP, Department of Pediatric Hematology and Oncology, 2 Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic marketa.zaliova@lfmotol.cuni.cz jan.zuna@lfmotol.cuni.cz.
authors.forename: Marketa
authors.initials: M
authors.lastname: Zaliova
authors.affiliation: Leukaemia Research Cytogenetics Group, Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Anthony V
authors.initials: AV
authors.lastname: Moorman
authors.affiliation: Centro Ricerca Tettamanti, Clinica Pediatrica, Università di Milano-Bicocca, Fondazione MBBM/Ospedale San Gerardo, Monza, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Cazzaniga
authors.affiliation: Pediatric Hematology and Oncology, Hannover Medical School, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Stanulla
authors.affiliation: University of New Mexico Cancer Center, Albuquerque, NM, USA.
authors.forename: Richard C
authors.initials: RC
authors.lastname: Harvey
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Kathryn G
authors.initials: KG
authors.lastname: Roberts
authors.affiliation: South Australia Health and Medical Research Institute, Adelaide, Australia.
authors.forename: Sue L
authors.initials: SL
authors.lastname: Heatley
authors.affiliation: Department of Pediatrics, Hematology-Oncology, Benioff Children's Hospital, and the Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA.
authors.forename: Mignon L
authors.initials: ML
authors.lastname: Loh
authors.affiliation: Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: Marina
authors.initials: M
authors.lastname: Konopleva
authors.affiliation: University of New Mexico Cancer Center, Albuquerque, NM, USA.
authors.forename: I-Ming
authors.initials: IM
authors.lastname: Chen
authors.affiliation: CLIP, Department of Pediatric Hematology and Oncology, 2 Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic.
authors.forename: Olga
authors.initials: O
authors.lastname: Zimmermannova
authors.affiliation: Leukaemia Research Cytogenetics Group, Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Claire
authors.initials: C
authors.lastname: Schwab
authors.affiliation: Department of Haematology, Our Lady's Children's Hospital, Dublin, Ireland.
authors.forename: Owen
authors.initials: O
authors.lastname: Smith
authors.affiliation: Department of Cancer Biology, Institut Paoli Calmettes, Marseille, France.
authors.forename: Marie-Joelle
authors.initials: MJ
authors.lastname: Mozziconacci
authors.affiliation: Department of Hematology, Institut Paoli Calmettes, Marseille, France.
authors.forename: Christian
authors.initials: C
authors.lastname: Chabannon
authors.affiliation: Department of Laboratory Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
authors.forename: Myungshin
authors.initials: M
authors.lastname: Kim
authors.affiliation: Department of Hematology, Leiden University Medical Center, The Netherlands.
authors.forename: J H
authors.initials: JH
authors.lastname: Frederik Falkenburg
authors.affiliation: Birmingham Children's Hospital, NHS Foundation Trust, UK.
authors.forename: Alice
authors.initials: A
authors.lastname: Norton
authors.affiliation: Department of Cytogenetics, Leicester Royal Infirmary NHS Trust, UK.
authors.forename: Karen
authors.initials: K
authors.lastname: Marshall
authors.affiliation: St. Anna Children's Hospital, Childrens Cancer Research Institute, Vienna, Austria.
authors.forename: Oskar A
authors.initials: OA
authors.lastname: Haas
authors.affiliation: CLIP, Department of Pediatric Hematology and Oncology, 2 Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic.
authors.forename: Julia
authors.initials: J
authors.lastname: Starkova
authors.affiliation: CLIP, Department of Pediatric Hematology and Oncology, 2 Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Stuchly
authors.affiliation: Department of Pediatrics and the Center for Childhood Cancer Research, Children's Hospital of Philadelphia and the University of Pennsylvania Perelman School of Medicine, PA, USA.
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Hunger
authors.affiliation: South Australia Health and Medical Research Institute, Adelaide, Australia.
authors.forename: Deborah
authors.initials: D
authors.lastname: White
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Charles G
authors.initials: CG
authors.lastname: Mullighan
authors.affiliation: University of New Mexico Cancer Center, Albuquerque, NM, USA.
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Willman
authors.affiliation: CLIP, Department of Pediatric Hematology and Oncology, 2 Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Stary
authors.affiliation: CLIP, Department of Pediatric Hematology and Oncology, 2 Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Trka
authors.affiliation: CLIP, Department of Pediatric Hematology and Oncology, 2 Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic marketa.zaliova@lfmotol.cuni.cz jan.zuna@lfmotol.cuni.cz.
authors.forename: Jan
authors.initials: J
authors.lastname: Zuna
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D017398:Alternative Splicing; D002648:Child; D002675:Child, Preschool; D016000:Cluster Analysis; D056915:DNA Copy Number Variations; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007223:Infant; D007938:Leukemia / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality / Q000628:therapy; D008297:Male; D008875:Middle Aged; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D059467:Transcriptome; D014178:Translocation, Genetic; D055815:Young Adult; D000097764:ETS Translocation Variant 6 Protein
chemical_list: D015514:Oncogene Proteins, Fusion; D011505:Protein-Tyrosine Kinases; C426234:TEL-ABL fusion protein, human; D000097764:ETS Translocation Variant 6 Protein