Prognostic relevance of integrated genetic profiling in adult T-cell acute lymphoblastic leukemia

Abstract

Adult T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic tumor associated with poor outcome. In this study, we analyzed the prognostic relevance of genetic alterations, immunophenotypic markers, and microarray gene expression signatures in a panel of 53 adult T-ALL patients treated in the Eastern Cooperative Oncology Group E2993 clinical trial. An early immature gene expression signature, the absence of bi-allelic TCRG deletion, CD13 surface expression, heterozygous deletions of the short arm of chromosome 17, and mutations in IDH1/IDH2 and DNMT3A genes are associated with poor prognosis in this series. In contrast, expression of CD8 or CD62L, homozygous deletion of CDKN2A/CDKN2B, NOTCH1 and/or FBXW7 mutations, and mutations or deletions in the BCL11B tumor suppressor gene were associated with improved overall survival. Importantly, the prognostic relevance of CD13 expression and homozygous CDKN2A/CDKN2B deletions was restricted to cortical and mature T-ALLs. Conversely, mutations in IDH1/IDH2 and DNMT3A were specifically associated with poor outcome in early immature adult T-ALLs. This trial was registered at www.clinicaltrials.gov as #NCT00002514.

Figure 1

Prognostic value of immature adult T-ALL. (A) Top 50 differentially expressed genes between early immature and cortical/mature adult T-ALL. Genes in the heat map are shown in rows, and each individual sample is shown in 1 column. The scale bar shows color-coded differential expression from the mean in standard deviation units, with red indicating higher levels and blue lower levels of expression. (B) Gene Set Enrichment Analysis of genes associated with pediatric ETP leukemias in early immature vs cortical/mature adult T-ALLs. (C) Kaplan-Meier survival curves in adult T-ALL patients treated in ECOG clinical trial ECOG2993 with early immature vs cortical/mature gene expression signatures.

Figure 2

Prognostic value of copy number defects in adult T-ALL. (A) Human chromosomal ideograms showing the areas of genetic gain and loss identified by aCGH in adult T-ALL. Red bars represent areas of gain. Light blue bars represent areas of heterozygous copy number loss, and dark blue bars indicate homozygous deletions. (B-D) Kaplan-Meier survival curves in adult T-ALL patients (B) with or without the absence of bi-allelic deletion of the TCRG locus (ABD); (C) with or without homozygous CDKN2A/CDKN2B deletion; and (D) with or without heterozygous TP53 (17q) deletion, treated in the ECOG2993 clinical trial.

Figure 3

Genetic and immunophenotypic characteristics of adult T-ALL. Schematic comparison of copy number lesions, genetic mutations, and surface marker expression between early immature and mature/cortical adult T-ALL. Solid circles represent positive leukemia samples. Data were not available for leukemia patients represented by gray filled circles. T-ALL oncogenic subtypes are based on aCGH alterations and microarray expression of T-ALL transcription factor oncogenes.

Figure 4

Prognostic value of somatic gene mutations in adult T-ALL. (A) Kaplan-Meier survival curve in adult T-ALLs treated in the ECOG2993 clinical trial with or without NOTCH1/FBXW7 mutations. (B) Kaplan-Meier survival curve in adult T-ALLs treated in the ECOG2993 clinical trial with or without BCL11B mutations/deletions. (C) Kaplan-Meier survival curve in adult T-ALLs treated in the ECOG2993 clinical trial with or without DNMT3A mutations. (D) Kaplan-Meier survival curves in adult T-ALLs treated in the ECOG2993 clinical trial with or without IDH1/IDH2 mutations, treated in the ECOG2993 clinical trial.

Figure 5

Prognostic value of cell surface markers in adult T-ALL. (A) Kaplan-Meier survival curves in adult T-ALLs treated in the ECOG2993 clinical trial according to CD13 expression. (B) Kaplan-Meier survival curves in adult T-ALLs treated in the ECOG2993 clinical trial according to CD8 expression. (C) Kaplan-Meier survival curves in adult T-ALLs treated in the ECOG2993 clinical trial according to CD62L antigen expression.

Figure 6

Risk stratification in early immature and cortical/mature adult T-ALL. (A) Kaplan-Meier survival curve of early immature adult T-ALLs treated in the ECOG2993 clinical trial according to CD13 expression. (B) Kaplan-Meier survival curve of cortical/mature adult T-ALLs treated in the ECOG2993 clinical trial according to CD13 expression. (C) Kaplan-Meier survival curve of cortical/mature adult T-ALLs treated in the ECOG2993 clinical trial according to the presence or absence of homozygous CDKN2A/CDKN2B deletion. (D) Kaplan-Meier survival curve of early immature adult T-ALLs treated in the ECOG2993 clinical trial according to the presence or absence of DNMT3A mutations. (E) Kaplan-Meier survival curve of early immature adult T-ALLs treated in the ECOG2993 clinical trial according to the presence or absence of IDH1/IDH2 mutations.