Tyrosine kinase fusion genes in pediatric BCR-ABL1-like acute lymphoblastic leukemia

// Judith M. Boer 1 , Elisabeth M.P. Steeghs 1 , João R.M. Marchante 1 , Aurélie Boeree 1 , James J. Beaudoin 1 , H. Berna Beverloo 2, 3 , Roland P. Kuiper 4 , Gabriele Escherich 5 , Vincent H.J. van der Velden 6 , C. Ellen van der Schoot 7 , Hester A. de Groot-Kruseman 3 , Rob Pieters 3, 8 , Monique L. den Boer 1, 3 1 Department of Pediatric Oncology/Hematology, Erasmus Medical Center, Sophia Children’s Hospital, Rotterdam, The Netherlands 2 Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands 3 Dutch Childhood Oncology Group (DCOG), The Hague, The Netherlands 4 Department of Human Genetics, Radboud University Medical Center and Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands 5 German Cooperative Study Group for Childhood Acute Lymphoblastic Leukemia (COALL), Hamburg, Germany 6 Department of Immunology, Erasmus Medical Center, Rotterdam, The Netherlands 7 Sanquin Research and Landsteiner Laboratory, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands 8 Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands Correspondence to: Monique L. den Boer, email: m.l.denboer@erasmusmc.nl 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 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.