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

Abstract

Philadelphia chromosome-like (Ph-like) acute lymphoblastic leukemia (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 patients with childhood B-lineage ALL 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 whom were excluded from additional analyses because of the presence of BCR-ABL1 (n = 46) or ETV6-RUNX1 (n = 11). Among the remaining 284 patients (20.4%), 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 those with CRLF2 rearrangement). Among the remaining patients, using reverse transcriptase polymerase chain reaction or transcriptome sequencing, we identified targetable ABL-class fusions (ABL1, ABL2, CSF1R, and PDGFRB) in 14.1%, EPOR rearrangements or JAK2 fusions in 8.8%, alterations activating other JAK-STAT signaling genes (IL7R, SH2B3, JAK1) in 6.3% or other kinases (FLT3, NTRK3, LYN) in 4.6%, and mutations involving the Ras pathway (KRAS, NRAS, NF1, PTPN11) in 6% of those with Ph-like ALL. We identified 8 new rearrangement partners for 4 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 implemented in Children's Oncology Group ALL trials.

Figure 1.

Algorithm used for analysis of patient cases. Testing pipeline developed for downstream characterization of low-density array⁺ (LDA⁺) patient cases for identification of specific genetic events to allocate subgroups for specific targeted therapies with ABL-class TKIs and JAK inhibitors. CNS, central nervous system; HR, high risk; mut, mutation; QNS, quantity not sufficient; R, rearrangement; SR, standard risk.

Figure 2.

Genetic alterations in patients with Ph-like ALL with CRLF2 rearrangement. (A) Genomic landscape of CRLF2 rearrrangements. (B) Protein plot of sequence mutations in JAK1 and JAK2.

Figure 3.

Genetic alterations in patients with Ph-like disease without CRLF2 rearrangement.

Figure 4.

Karyotype ideogram summary of actionable gene fusions identified to date in adult and pediatric high-risk B-ALL. 3′ Kinase gene partners are in bold.