Genetic alterations activating kinase and cytokine receptor signaling in high-risk acute lymphoblastic leukemia.
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abstract
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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.Copyright © 2012 Elsevier Inc. All rights reserved.
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keywords
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Animals
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Base Sequence
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Cell Transformation, Neoplastic
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DNA Mutational Analysis
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Enzyme Activation
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Gene Expression Regulation, Leukemic
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Gene Rearrangement
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Genetic Predisposition to Disease
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Humans
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Mice
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Molecular Sequence Data
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Mutation
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Oncogene Proteins, Fusion
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Philadelphia Chromosome
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Phosphorylation
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Precursor Cell Lymphoblastic Leukemia-Lymphoma
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Protein Kinase Inhibitors
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Protein-Tyrosine Kinases
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RNA, Messenger
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Receptor, Platelet-Derived Growth Factor beta
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Receptors, Cytokine
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Recurrence
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Risk Factors
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Sequence Deletion
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Signal Transduction
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Trans-Activators
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