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 BCRABL1- 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 BCRABL1- 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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Keywords BCR-ABL1-like, Minimal residual disease, Pediatric B cell precursor acute lymphoblastic leukemia, Tyrosine kinase fusion
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Journal Oncotarget
Grant This work was funded by the European Commission 7th Framework Programme; grant id fp7/261474 - EUROPEAN NETWORK for CANCER research in CHILDREN and ADOLESCENTS (ENCCA)
Boer, J.M, Steeghs, E.M.P. (Elisabeth M.P.), Marchante, J.R.M, Boeree, A. (Aurélie), Beaudoin, E.L, Beverloo, H.B, … den Boer, M.L. (2017). Tyrosine kinase fusion genes in pediatric BCR-ABL1-like acute lymphoblastic leukemia. Oncotarget, 8(3), 4618–4628. doi:10.18632/oncotarget.13492