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Abstract
A subgroup of pediatric acute T-lymphoblastic leukemia (T-ALL) was characterized by a gene expression profile comparable to that of early T-cell precursors (ETPs) with a highly unfavorable outcome. We have investigated clinical and molecular characteristics of the ETP-ALL subgroup in adult T-ALL. As ETP-ALL represents a subgroup of early T-ALL we particularly focused on this cohort and identified 178 adult patients enrolled in the German Acute Lymphoblastic Leukemia Multicenter studies (05/93–07/03). Of these, 32% (57/178) were classified as ETP-ALL based on their characteristic immunophenotype. The outcome of adults with ETP-ALL was poor with an overall survival of only 35% at 10 years, comparable to the inferior outcome of early T-ALL with 38%. The molecular characterization of adult ETP-ALL revealed distinct alterations with overexpression of stem cell-related genes (BAALC, IGFBP7, MN1, WT1). Interestingly, we found a low rate of NOTCH1 mutations and no FBXW7 mutations in adult ETP-ALL. In contrast, FLT3 mutations, rare in the overall cohort of T-ALL, were very frequent and nearly exclusively found in ETP-ALL characterized by a specific immunophenotype. These molecular characteristics provide biologic insights and implications with respect to innovative treatment strategies (for example, tyrosine kinase inhibitors) for this high-risk subgroup of adult ETP-ALL.
Highlights
T-cell precursors (ETPs) are intrathymic c-Kithi doublenegative (DN)[1] cells, which contribute to the development of T-lymphocytes.[1,2] These cells represent immature progenitors that have recently immigrated from the bone marrow to the thymus
early T-cell precursors-acute lymphoblastic leukemia (ETP-ALL) are distinguished by high expression of oncogenic transcription factors, including genes involved in the pathogenesis of acute T-lymphoblastic leukemia (T-ALL) like LMO1, LYL1 and ERG
This study was approved by the ethics board of the Johann Wolfgang immunophenotype of early T-ALL who were enrolled in the GMALL trials (05/93, 06/99, 07/03) between 1993 and 2008
Summary
T-cell precursors (ETPs) are intrathymic c-Kithi doublenegative (DN)[1] cells, which contribute to the development of T-lymphocytes.[1,2] These cells represent immature progenitors that have recently immigrated from the bone marrow to the thymus. A small subgroup of pediatric acute T-lymphoblastic leukemia (T-ALL) was described showing a gene expression profile closely linked to the expression signature of ETPs.[4,5] This subtype, termed ETP-ALL, is characterized by a specific immunophenotype: CD1aÀ, CD8À, CD5weak and expression of stem cell or myeloid markers. Some study groups utilize an initial leukocyte count above 100 000/nl as an adverse prognostic factor, the German Multicenter Study Group for Adult ALL (GMALL) applies risk stratification for T-ALL based on the immunophenotype.[7] On the basis of the results of earlier study protocols, early (sCD3À, CD1aÀ) T-ALL is regarded as a high-risk subgroup and alloSCT is recommended in first complete remission (CR).[7] patients with ETP-ALL, being exclusively found in the subgroup of early T-ALL, are already assigned towards alloSCT within the GMALL strategy.
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