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

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 consecuti...

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Veröffentlicht in:Blood Jg. 129; H. 25; S. 3352
Hauptverfasser: Reshmi, Shalini C, Harvey, Richard C, Roberts, Kathryn G, Stonerock, Eileen, Smith, Amy, Jenkins, Heather, Chen, I-Ming, Valentine, Marc, Liu, Yu, Li, Yongjin, Shao, Ying, Easton, John, Payne-Turner, Debbie, Gu, Zhaohui, Tran, Thai Hoa, Nguyen, Jonathan V, Devidas, Meenakshi, Dai, Yunfeng, Heerema, Nyla A, Carroll, 3rd, Andrew J, Raetz, Elizabeth A, Borowitz, Michael J, Wood, Brent L, Angiolillo, Anne L, Burke, Michael J, Salzer, Wanda L, Zweidler-McKay, Patrick A, Rabin, Karen R, Carroll, William L, Zhang, Jinghui, Loh, Mignon L, Mullighan, Charles G, Willman, Cheryl L, Gastier-Foster, Julie M, Hunger, Stephen P
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States 22.06.2017
Schlagworte:
Child
Female
Fusion Proteins, bcr-abl - genetics
Gene Expression Regulation, Leukemic
Gene Fusion
Humans
Interleukin-7 Receptor alpha Subunit - genetics
Janus Kinase 2 - genetics
Male
Mutation
Philadelphia Chromosome
Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - genetics
Protein Kinases - genetics
Receptors, Cytokine - genetics
Retrospective Studies
Transcriptome
ISSN:1528-0020, 1528-0020
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Zusammenfassung: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 - (n = 46) or - (n = 11). Among the remaining 284 patients (20.4%), overexpression and rearrangement of ( - or - ) were identified in 124 (43.7%), with concomitant genomic alterations activating the JAK-STAT pathway ( , , ) identified in 63 patients (50.8% of those with rearrangement). Among the remaining patients, using reverse transcriptase polymerase chain reaction or transcriptome sequencing, we identified targetable ABL-class fusions ( , , , and ) in 14.1%, rearrangements or fusions in 8.8%, alterations activating other JAK-STAT signaling genes ( , , ) in 6.3% or other kinases ( , , ) in 4.6%, and mutations involving the Ras pathway ( , , , ) 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.
Bibliographie:ObjectType-Article-2
SourceType-Scholarly Journals-1
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ISSN:1528-0020
1528-0020
DOI:10.1182/blood-2016-12-758979