Gene expression profiling in T-cell acute lymphoblastic leukemia☆
Section snippets
Transcription factor oncogenes and T-ALL
Major advances in understanding of the molecular basis of T-ALL have resulted from the study of rare, specific chromosomal translocations in leukemic cells. Recurrent chromosomal abnormalities in T-ALL typically juxtapose strong promoter elements responsible for high levels of expression of the T-cell receptor genes in T-cell precursors with genes encoding a small number of developmentally important transcription factors. Typical translocations juxtapose potent enhancers of T-cell receptor beta
Gene expression studies implicate a small subset of transcription factor oncogenes in the majority of T-ALL cases
Despite the rarity of chromosomal translocations that can activate oncogene expression in T-ALL, molecular studies have shown that at least one of these oncogene, TAL1, is regulated more broadly by mechanisms other than cis-acting chromosomal rearrangements.3 That TAL1 can be aberrantly expressed from both chromosomal alleles in T-ALL implicates activation through mutational mechanisms that affect upstream regulatory pathways. This observation also indicates the importance of pathways which
Gene expression signatures and T-ALL oncogenes
Gene expression profiling using DNA microarrays is a powerful and rapidly evolving tool to explore the transcriptional networks that regulate discrete cell populations on a genomic scale. The application of gene expression profiling in T-ALL should facilitate the in-depth analysis of regulatory networks within the molecular subgroups in this disease (class identification), and also permit the development of models to help predict responsiveness to chemotherapy (class distinction). In addition,
Gene expression signatures link T-ALL oncogenes to specific arrest of t-cell differentiation
T-cell development is a complex multistep process that involves the intrathymic differentiation, proliferation, and selection of T-cell precursors, resulting in the production of functional mature T cells.30 T-ALLs are derived from developing thymocytes, and as such, they share numerous cellular, immunophenotypic, and molecular properties with their normal cell counterparts.12 LYL1-positive T-ALL cases are characterized by the expression of early thymocyte genes, including CD34, BCL2, IL7R, and
MLL rearrangement signatures in T-ALL
The identification of biologic characteristics associated with different tumor types using gene expression analysis is not simple. The large amount of data provided by DNA arrays, the paucity of information about the functional role of most genes, and, in the case of the analysis of primary tumor samples, the limited amount of specimen available for complementary experimental approaches, all pose obstacles to our understanding the biology underlying differential gene expression. Yet, the
New molecular markers for prognosis prediction in T-ALL
DNA microarrays have provided multiparametric analysis on a genome-wide scale and have exponentially increased our power to recognize heterogeneity among different tumor samples. One of their most promising applications is the identification of markers to accurately predict outcome. Two different prognostic models based on different approaches have been developed from gene expression analysis in T-ALL. A hypothesis-driven approach that examines the prognostic impact of T-ALL transcription
Future directions
Gene expression profiling studies have prompted the recognition of clinically relevant, distinct molecular groups in T-ALL, and they have improved our understanding of the mechanisms of transformation of normal T-cell progenitor cells. Further progress in the molecular analysis of T-ALL will come from the comparison of tumor samples with normal cellular counterparts in the thymus and from the study of greater numbers of cases in the context of carefully conducted clinical trials. The direct
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2017, Clinical Lymphoma, Myeloma and LeukemiaActivation of the LMO2 oncogene through a somatically acquired neomorphic promoter in T-cell acute lymphoblastic leukemia
2017, BloodCitation Excerpt :Reported mechanisms of aberrant LMO2 expression in human T-ALL include recurrent chromosomal translocations, such as t(11;14)(p13;q11) and t(7;11)(q35;p13); cryptic deletions of an upstream negative regulatory region, as in del(11)(p12p13); and retroviral insertional mutagenesis at the LMO2 locus during gene therapy.7-11 Although ∼50% of T-ALL patients overexpress LMO2, only about 10% of patients have a detectable cytogenetic lesion.12 Notably, many of these patients will overexpress LMO2 from a single allele, a feature reminiscent of TAL1 overexpressing T-ALL cases driven by small somatic indel mutations that create binding sites for MYB, thus generating a neomorphic enhancer.13,14
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Supported in part by National Institutes of Health Grants No. CA 59571 and CA 68484, and a center grant from the Leukemia and Lymphoma Society. A.A.F. is a Fellow of the Leukemia and Lymphoma Society.