Immature MEF2C-dysregulated T-cell leukemia patients have an early T-cell precursor acute lymphoblastic leukemia gene signature and typically have non-rearranged T-cell receptors

Abstract

Three distinct immature T-cell acute lymphoblastic leukemia entities have been described including cases that express an early T-cell precursor immunophenotype or expression profile, immature MEF2C-dysregulated T-cell acute lymphoblastic leukemia cluster cases based on gene expression analysis (immature cluster) and cases that retain non-rearranged TRG@ loci. Early T-cell precursor acute lymphoblastic leukemia cases exclusively overlap with immature cluster samples based on the expression of early T-cell precursor acute lymphoblastic leukemia signature genes, indicating that both are featuring a single disease entity. Patients lacking TRG@ rearrangements represent only 40% of immature cluster cases, but no further evidence was found to suggest that cases with absence of bi-allelic TRG@ deletions reflect a distinct and even more immature disease entity. Immature cluster/early T-cell precursor acute lymphoblastic leukemia cases are strongly enriched for genes expressed in hematopoietic stem cells as well as genes expressed in normal early thymocyte progenitor or double negative-2A T-cell subsets. Identification of early T-cell precursor acute lymphoblastic leukemia cases solely by defined immunophenotypic criteria strongly underestimates the number of cases that have a corresponding gene signature. However, early T-cell precursor acute lymphoblastic leukemia samples correlate best with a CD1 negative, CD4 and CD8 double negative immunophenotype with expression of CD34 and/or myeloid markers CD13 or CD33. Unlike various other studies, immature cluster/early T-cell precursor acute lymphoblastic leukemia patients treated on the COALL-97 protocol did not have an overall inferior outcome, and demonstrated equal sensitivity levels to most conventional therapeutic drugs compared to other pediatric T-cell acute lymphoblastic leukemia patients.

Figure 1.

ETP-ALL patients express high MEF2C, LMO2 and LYL1 levels but not ERG or BAALC. The expression of (A) MEF2C (probe set 239966_at), (B) LMO1 (probe set 206718_at), (C) LMO2 (probe set 204249_s_at), (D) LYL1 (probe set 210044_s_at), (E) ERG (probe set 1563392_at), and (F) BAALC (probe set 222780_s_at) was based on VSN normalized microarray gene expression data for ETP-ALL (gray squares) and non-ETP-ALL cases (white squares). For the ETP-ALL subgroup, the ABD and non-ABD cases are indicated separately.

Figure 2.

ETP-ALL patients who were treated using the COALL-97 protocol were not associated with poor outcome. (A) Relapse-free survival (RFS) and (B) event-free survival (EFS) curves were generated for the COALL pediatric T-ALL patients. Shown are the RFS and EFS curves for ETP-ALL cases (black line) versus non-ETP-ALL cases (gray line). Vertical tick marks represent individual cases for which no further follow-up data is available.