Targetable kinase gene fusions in high risk B-ALL: a study from the Children's Oncology Group

Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is a high-risk subtype characterized by genomic alterations that activate cytokine receptor and kinase signaling. We examined the frequency and spectrum of targetable genetic lesions in a retrospective cohort of 1389 consecutively diagnosed childhood B-ALL patients with high-risk clinical features and/or elevated minimal residual disease at the end of remission induction therapy. The Ph-like gene expression profile was identified in 341 of 1389 patients, 57 of which were excluded from additional analysis because of the presence of BCR-ABL1 (n=46) or ETV6-RUNX1 (n=11). Among the remaining 284 (20.4%) patients, overexpression and rearrangement of CRLF2 ( IGH-CRLF2 or P2RY8-CRLF2 ) were identified in 124 (43.7%), with concomitant genomic alterations activating the JAK-STAT pathway ( JAK1 , JAK2 , IL7R ) identified in 63 patients (50.8% of CRLF2-rearranged cases). Of the remaining patients, using RT-PCR or transcriptome sequencing, we identified targetable ABL-class fusions ( ABL1 , ABL2 , CSF1R and PDGFRB ) in 14.1% of Ph-like ALL cases, EPOR rearrangements or JAK2 fusions (8.8%), alterations activating other JAK-STAT signaling genes ( IL7R , SH2B3 , JAK1 ; 6.3%) and other kinases ( FLT3 , NTRK3 , LYN ; 4.6%), and mutations involving the Ras pathway ( KRAS , NRAS , NF1 , PTPN11 ; 6%). We identified eight new rearrangement partners for four kinase genes previously reported to be rearranged in Ph-like ALL. The current findings provide support for the precision-medicine testing and treatment approach for Ph-like ALL that has been implemented in Children9s Oncology Group ALL trials.