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

Judith M Boer, Elisabeth M P Steeghs, João R M Marchante, Aurélie Boeree, James J Beaudoin, H Berna Beverloo, Roland P Kuiper, Gabriele Escherich, Vincent H J van der Velden, C Ellen van der Schoot, Hester A de Groot-Kruseman, Rob Pieters, Monique L den Boer

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)4618-4628
Number of pages11
JournalOncotarget
Volume8
Issue number3
DOIs
Publication statusPublished - 17 Jan 2017

Keywords

  • Adolescent
  • Cohort Studies
  • Female
  • Fusion Proteins, bcr-abl/genetics
  • Gene Deletion
  • Germany
  • Humans
  • Ikaros Transcription Factor/genetics
  • Intracellular Signaling Peptides and Proteins/genetics
  • Janus Kinase 2/genetics
  • Male
  • Mutation
  • Netherlands
  • Oligonucleotide Array Sequence Analysis
  • Oncogene Proteins, Fusion/genetics
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics
  • Protein-Tyrosine Kinases/genetics
  • Telomeric Repeat Binding Protein 2/genetics
  • Young Adult

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