TY - JOUR
T1 - Targetable kinase gene fusions in high-risk B-ALL
T2 - A study from the Children's Oncology Group
AU - Reshmi, Shalini C.
AU - Harvey, Richard C.
AU - Roberts, Kathryn G.
AU - Stonerock, Eileen
AU - Smith, Amy
AU - Jenkins, Heather
AU - Chen, I. Ming
AU - Valentine, Marc
AU - Liu, Yu
AU - Li, Yongjin
AU - Shao, Ying
AU - Easton, John
AU - Payne-Turner, Debbie
AU - Gu, Zhaohui
AU - Tran, Thai Hoa
AU - Nguyen, Jonathan V.
AU - Devidas, Meenakshi
AU - Dai, Yunfeng
AU - Heerema, Nyla A.
AU - Carroll, Andrew J.
AU - Raetz, Elizabeth A.
AU - Borowitz, Michael J.
AU - Wood, Brent L.
AU - Angiolillo, Anne L.
AU - Burke, Michael J.
AU - Salzer, Wanda L.
AU - Zweidler-McKay, Patrick A.
AU - Rabin, Karen R.
AU - Carroll, William L.
AU - Zhang, Jinghui
AU - Loh, Mignon L.
AU - Mullighan, Charles G.
AU - Willman, Cheryl L.
AU - Gastier-Foster, Julie M.
AU - Hunger, Stephen P.
N1 - Funding Information:
The authors wish to thank Erik Zmuda at Nationwide Children's Hospital for technical assistance and Joshua Stokes from Biomedical Communications at St. Jude Children's Research Hospital for the pie charts. This work was supported by grants from St. Baldrick's Foundation (S.P.H., C.G.M., and M.L.L.) the Leukemia Lymphoma Society (W.L.C., S.P.H., and C.G.M.), the National Institutes of Health, National Cancer Institute (U10 CA 180886, U10 CA 180899, and P30 CA021765), and the National Institutes of Health, National Institute of General Medical Sciences (P50 GM115279). M.L.L. is the Benioff Distinguished Chair of Children's Health. S.P.H. is the Jeffrey E. Perelman Distinguished Chair in Pediatrics at the Children's Hospital of Philadelphia. K.G.R. is an American Society of Hematology Scholar. The opinions and assertions contained herein are the private views of the authors and are not to be construed as the official policy or position of the US Government, the Department of Defense, the Department of the Air Force, or the US Food and Drug Administration.
Publisher Copyright:
© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.
PY - 2017/6/22
Y1 - 2017/6/22
N2 - Philadelphiachromosome-like(Ph-like) acutelymphoblasticleukemia(ALL) isahigh-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 diseaseatthe 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.
AB - Philadelphiachromosome-like(Ph-like) acutelymphoblasticleukemia(ALL) isahigh-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 diseaseatthe 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=85021677684&partnerID=8YFLogxK
U2 - 10.1182/blood-2016-12-758979
DO - 10.1182/blood-2016-12-758979
M3 - Article
C2 - 28408464
AN - SCOPUS:85021677684
SN - 0006-4971
VL - 129
SP - 3352
EP - 3361
JO - Blood
JF - Blood
IS - 25
ER -