Tyrosine kinome sequencing of pediatric acute lymphoblastic leukemia: a report from the Children's Oncology Group TARGET Project

• Published in: Blood 2013-01, Vol.121 (3), p.485-488
• Main Authors: Loh, Mignon L., Zhang, Jinghui, Harvey, Richard C., Roberts, Kathryn, Payne-Turner, Debbie, Kang, Huining, Wu, Gang, Chen, Xiang, Becksfort, Jared, Edmonson, Michael, Buetow, Kenneth H., Carroll, William L., Chen, I-Ming, Wood, Brent, Borowitz, Michael J., Devidas, Meenakshi, Gerhard, Daniela S., Bowman, Paul, Larsen, Eric, Winick, Naomi, Raetz, Elizabeth, Smith, Malcolm, Downing, James R., Willman, Cheryl L., Mullighan, Charles G., Hunger, Stephen P.
• Format: Article
• Language: English
• Subjects: Brief Report; Child; Child, Preschool; Disease-Free Survival; Female; fms-Like Tyrosine Kinase 3 - genetics; fms-Like Tyrosine Kinase 3 - metabolism; Gene Expression Regulation, Leukemic - physiology; Humans; Infant; Janus Kinase 1 - genetics; Janus Kinase 1 - metabolism; Janus Kinase 2 - genetics; Janus Kinase 2 - metabolism; Lymphoid Neoplasia; Male; Neoplasm, Residual - enzymology; Neoplasm, Residual - genetics; Neoplasm, Residual - mortality; Philadelphia Chromosome; Precursor Cell Lymphoblastic Leukemia-Lymphoma - enzymology; Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics; Precursor Cell Lymphoblastic Leukemia-Lymphoma - mortality; Protein-Tyrosine Kinases - genetics; Protein-Tyrosine Kinases - metabolism; Receptors, Cytokine - genetics; Receptors, Cytokine - metabolism; Receptors, Purinergic P2Y - genetics; Receptors, Purinergic P2Y - metabolism; Signal Transduction - genetics; Transcriptome
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2012-04-422691

One recently identified subtype of pediatric B-precursor acute lymphoblastic leukemia (ALL) has been termed BCR-ABL1–like or Ph-like because of similarity of the gene expression profile to BCR-ABL1 positive ALL suggesting the presence of lesions activating tyrosine kinases, frequent alteration of IKZF1, and poor outcome. Prior studies demonstrated that approximately half of these patients had genomic lesions leading to CRLF2 overexpression, with half of such cases harboring somatic mutations in the Janus kinases JAK1 and JAK2. To determine whether mutations in other tyrosine kinases might also occur in ALL, we sequenced the tyrosine kinome and downstream signaling genes in 45 high-risk pediatric ALL cases with either a Ph-like gene expression profile or other alterations suggestive of activated kinase signaling. Aside from JAK mutations and 1 FLT3 mutation, no somatic mutations were found in any other tyrosine kinases, suggesting that alternative mechanisms are responsible for activated kinase signaling in high-risk ALL. •Pediatric B-ALL cases with a gene expression signature similar to that of Philadelphia chromosome positive (Ph-like ALL) have a high risk of relapse.•Point mutations in tyrosine kinase genes are rare in pediatric Ph-like or other high-risk ALL cases except for in Janus kinase (JAK) family genes or rarely in FLT3.