Genomic profiling of high-risk acute lymphoblastic leukemia
ABSTRACT Acute lymphoblastic leukemia (ALL) is a heterogeneous disease comprising multiple subtypes with different genetic alterations and responses to therapy. Recent genome-wide profiling studies of ALL have identified a number of novel genetic alterations that target key cellular pathways in lymphoid growth and differentiation and are associated with treatment outcome. Notably, genetic alteration of the lymphoid transcription factor gene IKZF1 is a hallmark of multiple subtypes of ALL with poor prognosis, including BCR-ABL1-positive lymphoid leukemia and a subset of 'BCR-ABL1-like' ALL cases that, in addition to IKZF1 alteration, harbor genetic mutations resulting in aberrant lymphoid cytokine receptor signaling, including activating mutations of Janus kinases and rearrangement of cytokine receptor-like factor 2 (CRLF2). Recent insights from genome-wide profiling studies of B-progenitor ALL and the potential for new therapeutic approaches in high-risk disease are discussed.
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ABSTRACT: We discuss the methods of using natural language processing technologies for lexical semantic knowledge acquisition. The basic idea is to use shallow (while not complete) natural language processing technologies to acquire domain (while not general) lexical semantic knowledge. These acquiring approaches are based on domain corpus and are transportable among domains. As an application example, through an analysis to the need of 2008 Digital Olympics to multilingual language resources, we try to construct an Olympic-oriented lexical semantic knowledge base in the field of sports, where the above NLP technologies are used to build a human-machine interactive lexical semantic knowledge base construction platform.Natural Language Processing and Knowledge Engineering, 2003. Proceedings. 2003 International Conference on; 11/2003
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ABSTRACT: Recent genomic analyses of childhood and adult B-precursor acute lymphoblastic leukemia (ALL) samples have identified novel genetic alterations in essential lymphoid development and signal transduction pathways, providing insight into the pathogenesis of high-risk ALL associated with treatment failure. Particular advances have been made in unraveling the genetics of ALL associated with overexpression of the cytokine receptor-like factor 2 gene (CRLF2), which is frequently accompanied by simultaneous activating mutations in genes encoding Ikaros (IKZF1), Janus kinase 1 (JAK1) and Janus kinase 2 (JAK2), and/or the IL-7 receptor alpha chain (IL7RA). Children and adults with high-risk CRLF2-overexpressing ALL have high rates of relapse and dismal overall survival. Various groups have thus attempted to characterize the biochemical consequences of these genetic lesions via preclinical models with the goal of identifying targets for new therapies. These studies provide early data suggesting the promise of signal transduction inhibitors (STIs) of the JAK/STAT and PI3K pathways for CRLF2-overexpressing ALL. Additional research efforts continue to elucidate these aberrant signaling networks to provide rationale for bringing STIs into the clinic for these high-risk patients. This review highlights the current knowledge of the incidence, prognostic significance, and biology of CRLF2-overexpressing ALL and future directions for development of targeted therapies.Critical reviews in oncogenesis 01/2011; 16(1-2):13-24. DOI:10.1615/CritRevOncog.v16.i1-2.30
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ABSTRACT: Despite impressive advances in cure rates for childhood acute lymphoblastic leukemia (ALL), ALL remains the leading cause of disease-related death in young people and new therapeutic approaches directed against rational therapeutic targets are urgently required to improve treatment outcomes. This is particularly true for ALL in older children, adolescents, and adults, in whom treatment outcomes are markedly inferior to those of young children. A major goal of current leukemia research is to use comprehensive genomic analysis of the leukemic cell genome, transcriptome, and epigenome to identify critical new genomic alterations that drive leukemogenesis and influence responsiveness to therapy. Genomic analyses in childhood ALL have been remarkably informative and have identified a number of new structural genetic alterations that play important roles in the establishment of the leukemic clone and determine risk of relapse. Notably, many high-risk ALL cases harbor loss-of-function and dominant mutations of genes that encode transcriptional regulators of lymphoid development coupled with mutations that result in activation of cytokine receptor and kinase signaling pathways. These advances have resulted in new diagnostic approaches and therapeutic trials in ALL. This review will discuss these advances and outline challenges for future studies, including the potential role of genome-wide sequencing approaches and the need for detailed studies of the genetics of ALL in the adolescent and young adult population.06/2011; 1(2):77-86. DOI:10.1089/jayao.2011.0012