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Blood. 2017 Jun 22;129(25):3352-3361. doi: 10.1182/blood-2016-12-758979. Epub 2017 Apr 13.

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

Author information

1
Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH.
2
Department of Pathology, The Ohio State University College of Medicine, Columbus, OH.
3
University of New Mexico Cancer Center, Albuquerque, NM.
4
Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN.
5
Comprehensive Cancer Center, The Ohio State University College of Medicine, Columbus, OH.
6
Department of Cytogenetics and.
7
Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN.
8
Department of Pediatrics, UCSF Benioff Children's Hospital and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA.
9
Department of Biostatistics, University of Florida, Gainesville, FL.
10
Department of Genetics, University of Alabama at Birmingham, Birmingham, AL.
11
Department of Pediatrics, University of Utah, Salt Lake City, UT.
12
Department of Pathology, Johns Hopkins University, Baltimore, MD.
13
Seattle Children's Hospital, Seattle, WA.
14
Children's National Medical Center, Washington, DC.
15
Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI.
16
US Army Medical Research and Materiel Command, Fort Detrick, MD.
17
Department of Pediatrics, MD Anderson Cancer Center, Houston, TX.
18
Department of Pediatrics, Baylor College of Medicine, Houston, TX.
19
Perlmutter Cancer Center, NYU Langone Medical Center, New York, NY.
20
Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH; and.
21
Department of Pediatrics, Children's Hospital of Philadelphia and Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.

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.

PMID:
28408464
PMCID:
PMC5482101
DOI:
10.1182/blood-2016-12-758979
[Indexed for MEDLINE]
Free PMC Article

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