title: Tyrosine kinase fusion genes in pediatric BCR-ABL1-like acute lymphoblastic leukemia.
abstract: Approximately 15% of pediatric B cell precursor acute lymphoblastic leukemia (BCP-ALL) is characterized by gene expression similar to that of BCR-ABL1-positive disease and unfavorable prognosis. This BCR-ABL1-like subtype shows a high frequency of B-cell development gene aberrations and tyrosine kinase-activating lesions. To evaluate the clinical significance of tyrosine kinase gene fusions in children with BCP-ALL, we studied the frequency of recently identified tyrosine kinase fusions, associated genetic features, and prognosis in a representative Dutch/German cohort. We identified 14 tyrosine kinase fusions among 77 BCR-ABL1-like cases (18%) and none among 76 non-BCR-ABL1-like B-other cases. Novel exon fusions were identified for RCSD1-ABL2 and TERF2-JAK2. JAK2 mutation was mutually exclusive with tyrosine kinase fusions and only occurred in cases with high CRLF2 expression. The non/late response rate and levels of minimal residual disease in the fusion-positive BCR-ABL1-like group were higher than in the non-BCR-ABL1-like B-others (p<0.01), and also higher, albeit not statistically significant, compared with the fusion-negative BCR-ABL1-like group. The 8-year cumulative incidence of relapse in the fusion-positive BCR-ABL1-like group (35%) was comparable with that in the fusion-negative BCR-ABL1-like group (35%), and worse than in the non-BCR-ABL1-like B-other group (17%, p=0.07). IKZF1 deletions, predominantly other than the dominant-negative isoform and full deletion, co-occurred with tyrosine kinase fusions. This study shows that tyrosine kinase fusion-positive cases are a high-risk subtype of BCP-ALL, which warrants further studies with specific kinase inhibitors to improve outcome.
authors.affiliation: Department of Pediatric Oncology/Hematology, Erasmus Medical Center, Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: Judith M
authors.initials: JM
authors.lastname: Boer
authors.affiliation: Department of Pediatric Oncology/Hematology, Erasmus Medical Center, Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: Elisabeth M P
authors.initials: EM
authors.lastname: Steeghs
authors.affiliation: Department of Pediatric Oncology/Hematology, Erasmus Medical Center, Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: João R M
authors.initials: JR
authors.lastname: Marchante
authors.affiliation: Department of Pediatric Oncology/Hematology, Erasmus Medical Center, Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Boeree
authors.affiliation: Department of Pediatric Oncology/Hematology, Erasmus Medical Center, Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: James J
authors.initials: JJ
authors.lastname: Beaudoin
authors.affiliation: Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands.|Dutch Childhood Oncology Group (DCOG), The Hague, The Netherlands.
authors.forename: H Berna
authors.initials: HB
authors.lastname: Beverloo
authors.affiliation: Department of Human Genetics, Radboud University Medical Center and Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands.
authors.forename: Roland P
authors.initials: RP
authors.lastname: Kuiper
authors.affiliation: German Cooperative Study Group for Childhood Acute Lymphoblastic Leukemia (COALL), Hamburg, Germany.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Escherich
authors.affiliation: Department of Immunology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Vincent H J
authors.initials: VH
authors.lastname: van der Velden
authors.affiliation: Sanquin Research and Landsteiner Laboratory, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: C Ellen
authors.initials: CE
authors.lastname: van der Schoot
authors.affiliation: Dutch Childhood Oncology Group (DCOG), The Hague, The Netherlands.
authors.forename: Hester A
authors.initials: HA
authors.lastname: de Groot-Kruseman
authors.affiliation: Dutch Childhood Oncology Group (DCOG), The Hague, The Netherlands.|Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.
authors.forename: Rob
authors.initials: R
authors.lastname: Pieters
authors.affiliation: Department of Pediatric Oncology/Hematology, Erasmus Medical Center, Sophia Children's Hospital, Rotterdam, The Netherlands.|Dutch Childhood Oncology Group (DCOG), The Hague, The Netherlands.
authors.forename: Monique L
authors.initials: ML
authors.lastname: den Boer
mesh_terms: D000293:Adolescent; D015331:Cohort Studies; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000235:genetics*; D017353:Gene Deletion; D005858:Germany; D006801:Humans; D051740:Ikaros Transcription Factor / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D053614:Janus Kinase 2 / Q000235:genetics; D008297:Male; D009154:Mutation; D009426:Netherlands; D020411:Oligonucleotide Array Sequence Analysis; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D035341:Telomeric Repeat Binding Protein 2 / Q000235:genetics; D055815:Young Adult
chemical_list: C581634:BCR-ABL1 fusion protein, human; C497239:IKZF1 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D015514:Oncogene Proteins, Fusion; C506059:RCSD1 protein, human; C504753:TERF2 protein, human; D035341:Telomeric Repeat Binding Protein 2; D051740:Ikaros Transcription Factor; C426236:ARG tyrosine kinase; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; C507924:JAK2 protein, human; D053614:Janus Kinase 2
keywords: BCR-ABL1-like; minimal residual disease; pediatric B cell precursor acute lymphoblastic leukemia; tyrosine kinase fusion