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

• DOI: 10.1016/j.ccr.2012.06.005
• Publication Date: 2012-08-13T15:34:55Z
• Authors: Kathryn G. Roberts; Ryan D. Morin; Jinghui Zhang; Martin Hirst; Yongjun Zhao; Xiaoping Su; Shann-Ching Chen; Debbie Payne-Turner; Michelle L. Churc...; Richard C. Harvey; Xiang Chen; Corynn Kasap; Chunhua Yan; Jared Becksfort; Richard P. Finney; David T. Teachey; Shannon L. Maude; Kane Tse; Richard Moore; Steven Jones; Karen Mungall; Inanc Birol; Michael N. Edmonson; Ying Hu; Kenneth E. Buetow; I-Ming Chen; William L. Carroll; Lei Wei; Jing Ma; Maria Kleppe; Ross L. Levine; Guillermo Garcia-...; Eric Larsen; Neil P. Shah; Meenakshi Devidas; Gregory Reaman; Malcolm Smith; Steven W. Paugh; William E. Evans; Stephan A. Grupp; Sima Jeha; Ching-Hon Pui; Daniela S. Gerhard; James R. Downing; Cheryl L. Willman; Mignon Loh; Stephen P. Hunger; Marco A. Marra; Charles G. Mullighan
• Keywords: Cancer Research; Oncogene Proteins, Fusion; Messenger; DNA Mutational Analysis; Cell Transformation; Mice; Recurrence; Risk Factors; Receptors; 2.1 Biological and endogenous factors; Philadelphia Chromosome; Aetiology; Phosphorylation; Cancer; Sequence Deletion; Pediatric; Leukemic; Oncogene Proteins; Gene Rearrangement; 0303 health sciences; Gene Expression Regulation, Leukemic; leukemia; gene expression regulation; Hematology; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Protein-Tyrosine Kinases; Platelet-Derived Growth Factor beta; 3. Good health; Cell Transformation, Neoplastic; Oncology; Biotechnology; Receptor; Signal Transduction; Pediatric Research Initiative; 572; Childhood Leukemia; Pediatric Cancer; Oncology and Carcinogenesis; Molecular Sequence Data; Protein kinase inhibitors; Receptor, Platelet-Derived Growth Factor beta; 03 medical and health sciences; Rare Diseases; Genetics; Animals; Humans; Genetic Predisposition to Disease; Oncology & Carcinogenesis; RNA, Messenger; Fusion; Cytokine; Protein Kinase Inhibitors; Neoplastic; Base Sequence; Human Genome; Neurosciences; Cell Biology; Enzyme Activation; Orphan Drug; Gene Expression Regulation; Mutation; Trans-Activators; RNA

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.