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Targetable kinase gene fusions in high-risk B-ALL: a study from the Children's Oncology Group.
Blood 2017; 129(25):3352-3361Blood

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.

Authors+Show Affiliations

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

Pub Type(s)

Clinical Trial
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

28408464

Citation

Reshmi, Shalini C., et al. "Targetable Kinase Gene Fusions in High-risk B-ALL: a Study From the Children's Oncology Group." Blood, vol. 129, no. 25, 2017, pp. 3352-3361.
Reshmi SC, Harvey RC, Roberts KG, et al. Targetable kinase gene fusions in high-risk B-ALL: a study from the Children's Oncology Group. Blood. 2017;129(25):3352-3361.
Reshmi, S. C., Harvey, R. C., Roberts, K. G., Stonerock, E., Smith, A., Jenkins, H., ... Hunger, S. P. (2017). Targetable kinase gene fusions in high-risk B-ALL: a study from the Children's Oncology Group. Blood, 129(25), pp. 3352-3361. doi:10.1182/blood-2016-12-758979.
Reshmi SC, et al. Targetable Kinase Gene Fusions in High-risk B-ALL: a Study From the Children's Oncology Group. Blood. 2017 06 22;129(25):3352-3361. PubMed PMID: 28408464.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Targetable kinase gene fusions in high-risk B-ALL: 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,3rd 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, Y1 - 2017/04/13/ PY - 2016/12/23/received PY - 2017/04/09/accepted PY - 2017/4/15/pubmed PY - 2017/8/29/medline PY - 2017/4/15/entrez SP - 3352 EP - 3361 JF - Blood JO - Blood VL - 129 IS - 25 N2 - 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. SN - 1528-0020 UR - https://www.unboundmedicine.com/medline/citation/28408464/Targetable_kinase_gene_fusions_in_high_risk_B_ALL:_a_study_from_the_Children's_Oncology_Group_ L2 - http://www.bloodjournal.org/cgi/pmidlookup?view=long&pmid=28408464 DB - PRIME DP - Unbound Medicine ER -