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.
Highlights
Children with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) with the BCR-ABL1 fusion gene form a small patient group with a poor prognosis, which has been substantially improved in recent treatment protocols with the addition of imatinib and other tyrosine kinase inhibitors [1,2]
We focus on tyrosine kinase fusion genes because they are most similar to the well-known BCR-ABL1 fusion gene and expected to be clonal leukemia drivers
We identified ABL/JAK class tyrosine kinase fusion genes in 14/153 (9%) of DCOG/COALL B-other cases and these fusions were restricted to the BCRABL1-like B-other subgroup
Summary
Children with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) with the BCR-ABL1 fusion gene form a small patient group with a poor prognosis, which has been substantially improved in recent treatment protocols with the addition of imatinib and other tyrosine kinase inhibitors [1,2]. 15% of cases of BCP-ALL are characterized by a gene expression signature similar to that of BCR-ABL1-positive disease and an unfavorable prognosis [3,4]. This BCR-ABL1like subtype is found in approximately 50% of so-called B-other cases, which are BCP-ALL cases negative for the sentinel cytogenetic lesions BCR-ABL1, ETV6RUNX1, TCF3-PBX1, rearrangement of MLL, or high hyperdiploidy (51-65 chromosomes). Detection of tyrosine kinase fusions could guide targeted treatment with tyrosine kinase inhibitors and improve outcome in a similar way as currently for BCR-ABL1-positive patients
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