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Genetic Alterations Activating Kinase and Cytokine Receptor Signaling in High-Risk Acute Lymphoblastic Leukemia

2012; Cell Press; Volume: 22; Issue: 2 Linguagem: Inglês

10.1016/j.ccr.2012.06.005

1878-3686

Kathryn G. Roberts, Ryan D. Morin, Jinghui Zhang, Martin Hirst, Yongjun Zhao, Xiaoping Su, Shann-Ching Chen, Debbie Payne-Turner, Michelle L. Churchman, Richard C. Harvey, Xiang Chen, Corynn Kasap, Chunhua Yan, Jared Becksfort, Richard P. Finney, David T. Teachey, Shannon L. Maude, Kane Tse, Richard A. Moore, Steven J.M. Jones, Karen Mungall, İnanç Birol, Michael N. Edmonson, Ying Hu, Kenneth Buetow, I‐Ming Chen, William L. Carroll, Lei Wei, Jing Ma, Maria Kleppe, Ross L. Levine, Guillermo Garcia‐Manero, Eric Larsen, Neil P. Shah, Meenakshi Devidas, Gregory H. Reaman, Malcolm A. Smith, Steven W. Paugh, William E. Evans, Stephan A. Grupp, Sima Jeha, Ching‐Hon Pui, Daniela S. Gerhard, J R Downing, Cheryl L. Willman, Mignon L. Loh, Stephen P. Hunger, Marco A. Marra, Charles G. Mullighan,

Acute Myeloid Leukemia Research

Genomic profiling has identified a subtype of high-risk B-progenitor acute lymphoblastic leukemia (B-ALL) with alteration of IKZF1, a gene expression profile similar to BCR-ABL1-positive ALL and poor outcome (Ph-like ALL). The genetic alterations that activate kinase signaling in Ph-like ALL are poorly understood. We performed transcriptome and whole genome sequencing on 15 cases of Ph-like ALL and identified rearrangements involving ABL1, JAK2, PDGFRB, CRLF2, and EPOR, activating mutations of IL7R and FLT3, and deletion of SH2B3, which encodes the JAK2-negative regulator LNK. Importantly, several of these alterations induce transformation that is attenuated with tyrosine kinase inhibitors, suggesting the treatment outcome of these patients may be improved with targeted therapy.