Tyrosine kinase fusion genes in pediatric BCR-ABL1-like acute lymphoblastic leukemia
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Judith M. Boer1, Elisabeth M.P. Steeghs1, João R.M. Marchante1, Aurélie Boeree1, James J. Beaudoin1, H. Berna Beverloo2,3, Roland P. Kuiper4, Gabriele Escherich5, Vincent H.J. van der Velden6, C. Ellen van der Schoot7, Hester A. de Groot-Kruseman3, Rob Pieters3,8, Monique L. den Boer1,3
1Department of Pediatric Oncology/Hematology, Erasmus Medical Center, Sophia Children’s Hospital, Rotterdam, The Netherlands
2Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands
3Dutch Childhood Oncology Group (DCOG), The Hague, The Netherlands
4Department of Human Genetics, Radboud University Medical Center and Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands
5German Cooperative Study Group for Childhood Acute Lymphoblastic Leukemia (COALL), Hamburg, Germany
6Department of Immunology, Erasmus Medical Center, Rotterdam, The Netherlands
7Sanquin Research and Landsteiner Laboratory, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands
8Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
Monique L. den Boer, email: [email protected]
Keywords: BCR-ABL1-like, pediatric B cell precursor acute lymphoblastic leukemia, tyrosine kinase fusion, minimal residual disease
Received: September 24, 2016 Accepted: October 29, 2016 Published: November 22, 2016
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.
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