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

Shalini C. Reshmi, Richard C. Harvey, Kathryn G. Roberts, Eileen Stonerock, Amy Smith, Heather Jenkins, I-Ming Chen, Marc Valentine, Yu Liu, Yongjin Li, Ying Shao, John Easton, Debbie Payne-Turner, Thai Hoa Tran, Jonathan V. Nguyen, Meenakshi Devidas, Yunfeng Dai, Nyla A. Heerema, Andrew J. Carroll III, Elizabeth A. Raetz, Michael J. Borowitz, Brent L. Wood, Anne L. Angiolillo, Michael J. Burke, Wanda L. Salzer, Patrick A. Zweidler-McKay, Karen R. Rabin, William L. Carroll, Jinghui Zhang, Mignon L. Loh, Charles G. Mullighan, Cheryl L. Willman, Julie M. Gastier-Foster and Stephen P. Hunger

Key points

  • 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.


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 Children's Oncology Group ALL trials.

  • Submitted December 27, 2016.
  • Accepted April 9, 2017.