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 - 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 -