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

• Published in: Blood Vol. 129; no. 25; pp. 3352 - 3361
• Main Authors: Reshmi, Shalini C., Harvey, Richard C., Roberts, Kathryn G., Stonerock, Eileen, Smith, Amy, Jenkins, Heather, Chen, I-Ming, Valentine, Marc, Liu, Yu, Li, Yongjin, Shao, Ying, Easton, John, Payne-Turner, Debbie, Gu, Zhaohui, Tran, Thai Hoa, Nguyen, Jonathan V., Devidas, Meenakshi, Dai, Yunfeng, Heerema, Nyla A., Carroll, Andrew J., Raetz, Elizabeth A., Borowitz, Michael J., Wood, Brent L., Angiolillo, Anne L., Burke, Michael J., Salzer, Wanda L., Zweidler-McKay, Patrick A., Rabin, Karen R., Carroll, William L., Zhang, Jinghui, Loh, Mignon L., Mullighan, Charles G., Willman, Cheryl L., Gastier-Foster, Julie M., Hunger, Stephen P.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 22.06.2017; American Society of Hematology
• Subjects: Child; Female; Fusion Proteins, bcr-abl - genetics; Gene Expression Regulation, Leukemic; Gene Fusion; Humans; Interleukin-7 Receptor alpha Subunit - genetics; Janus Kinase 2 - genetics; Lymphoid Neoplasia; Male; Mutation; Philadelphia Chromosome; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - genetics; Protein Kinases - genetics; Receptors, Cytokine - genetics; Retrospective Studies; Transcriptome
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2016-12-758979

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. •Ph-like ALL is characterized by a diverse array of genetic alterations activating cytokine receptor and tyrosine kinase signaling.•Pediatric patients with Ph-like ALL can be identified in real time for effective treatment stratification.