Fast track — ArticlesEarly T-cell precursor leukaemia: a subtype of very high-risk acute lymphoblastic leukaemia
Introduction
T-cell acute lymphoblastic leukaemia (T-ALL) is a malignant clonal expansion of immature T cells that accounts for 10–15% of childhood and 25% of adult ALL cases. With wider use of intensive chemotherapy, the prognosis for childhood T-ALL has improved remarkably: nearly 80% of patients can currently be cured.1, 2 Further gains in treatment outcome will require methods to identify patients who continue to fail on contemporary protocols, so that alternative therapy can be introduced as early as possible. Demographic and clinical presenting features, such as older age and a high leucocyte count at diagnosis, are now regarded as unreliable predictors of outcome in patients with T-ALL treated with intensive chemotherapy;2, 3 cell-marker profiling has led to conflicting conclusions about its prognostic significance.3, 4, 5, 6 More recent studies have provided insights into the genetic abnormalities underlying T-ALL development, some of which seem to correlate with prognosis.7, 8, 9, 10 However, the prognostic associations of molecular abnormalities in T-ALL are not sufficiently compelling to justify their use in treatment planning.
Early T-cell precursors (ETPs) are a subset of thymocytes representing recent immigrants from the bone marrow to the thymus; they retain multilineage differentiation potential, suggesting their direct derivation from haemopoietic stem cells.11, 12, 13 We postulated that a proportion of T-ALL cases originate from oncogenically transformed ETPs and might therefore respond poorly to lymphoid-cell-directed chemotherapy. To test these predictions, we used a set of genes that are differentially expressed in ETPs11, 14, 15, 16 to identify cases of ETP leukaemia and then did a comprehensive study to establish the biological and clinical features of these leukaemias.
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Patients and treatment
139 consecutive patients with T-ALL (median age 8·8 years [range 0·5–18·9]) were enrolled in Total Therapy Studies XIII,17 XIV,18 and XV2 at St Jude Children's Research Hospital in Memphis, TN, USA, between Jan 10, 1992, and Dec 14, 2006. The diagnosis of T-ALL was made by at least two expert pathologists. In all 139 patients, leukaemic lymphoblasts had ALL L1 or L2 morphology, with less than 3% of lymphoblasts expressing cytochemical myeloperoxidase; none of the cases of T-ALL showed Auer
Results
By use of a set of genes shown to be differentially expressed in ETPs compared with more mature thymic subpopulations (webappendix),11, 14, 15, 16 we searched for leukaemias with an ETP-related gene profile in 55 newly diagnosed cases of T-ALL (figure 1). By unsupervised clustering analysis, we identified a cluster of 13 cases with gene-expression profiles that strongly resembled those described for ETPs (figure 2). Overexpressed genes in this group included CD44, CD34, KIT, GATA2, CEPBA, SPI1,
Discussion
We have identified a unique biological subtype of childhood leukaemia, ETP-ALL, which is associated with a high risk of remission induction failure or relapse in patients treated with contemporary protocols of intensive chemotherapy for ALL. We used the gene-expression profile of normal ETP to identify their leukaemic counterparts and define their immunophenotype. ETP-ALL cases have characteristic gene-expression profiles, an increased number and size of genomic lesions, denoting genomic
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