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

• DOI: 10.18632/oncotarget.13492
• Publication Date: 2016-11-22T20:18:30Z
• Authors: Judith M. Boer; Elisabeth M.P. St...; João R.M. Marchante; Aurélie Boeree; James J. Beaudoin; H. Berna Beverloo; Roland P. Kuiper; Gabriele Escherich; Vincent H.J. van ...; C. Ellen van der ...; Hester A. de Groo...; Rob Pieters; Monique L. den Boer
• Keywords: Male; Adolescent; Oncogene Proteins, Fusion; Fusion Proteins, bcr-abl; Intracellular Signaling Peptides and Proteins; EMC MM-02-54-03; Janus Kinase 2; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Protein-Tyrosine Kinases; EMC MM-02-72-01; 3. Good health; Cohort Studies; Ikaros Transcription Factor; Young Adult; Radboudumc 14: Tumours of the digestive tract RIMLS: Radboud Institute for Molecular Life Sciences; Germany; Mutation; Humans; Female; Telomeric Repeat Binding Protein 2; Gene Deletion; Research Paper; Netherlands; Oligonucleotide Array Sequence Analysis

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.