MEF2C as Novel Oncogene for Early T-Cell Precursor (ETP) Leukemia

Abstract 9

To identify novel oncogenic pathways in T-cell acute lymphoblastic leukemia (T-ALL), we combined expression profiling of 117 pediatric patient samples and detailed molecular cytogenetic analyses. Using unsupervised and supervised analyses, we identified a T-ALL cluster that was associated with an immature immunophenotype (CD1⁻, CD4⁻, CD8⁻), frequent expression of CD34 and co-expression of the myeloid markers CD13/CD33. Patients in this cluster lacked any of the known oncogenic rearrangements, but ectopically expressed MEF2C, which was recently demonstrated as an important transcription factor for T-cell development¹. Molecular-cytogenetic analyses including the Chromatine Conformation Capture on Chip (4C) method revealed novel rearrangements of the MEF2C locus at 5q14, rearrangement of transcription factors that target MEF2C (PU.1, NKX2-5, RUNX1) or MEF2C-associated cofactors (NCOA2/GRIP1) in about half of the patients in this cluster. Four out of the 6 rearrangements identified have never been observed before in human cancer. Nearly all of these patients in this cluster could be predicted by the early T-cell precursor (ETP) signature² using PAM statistics. This indicates that MEF2C may represent the oncogene for ETP T-ALL, an entity that has been associated with poor outcome². Inhibition of MEF2C in a cell line model system provoked relieve of developmental arrest, indicating that ectopic MEF2C expression blocks T-cell development at an early stage. We demonstrated that MEF2C is a transcriptional regulator for many differentially expressed genes that were associated with the immature cluster including LYL1 and LMO2. Although LYL1 has been suggested as potential oncogene for immature T-ALL cases³, oncogenic rearrangements were never identified in T-ALL cases with immature immunophenotype. Our data therefore imply that high expression of LYL1 (and LMO2) is part of a pathogenic pathway for immature T-ALL that is regulated by the MEF2C oncogene.

1 Stehling-Sun, S., Dade, J., Nutt, S. L., DeKoter, R. P. & Camargo, F. D. Regulation of lymphoid versus myeloid fate ’choice’ by the transcription factor Mef2c. Nat Immunol 10, 289–296, (2009).

2 Coustan-Smith, E. et al. Early T-cell precursor leukaemia: a subtype of very high-risk acute lymphoblastic leukaemia. Lancet Oncol 10, 147–156, (2009).

3 Ferrando, A. A. et al. Gene expression signatures define novel oncogenic pathways in T cell acute lymphoblastic leukemia. Cancer Cell 1, 75–87 (2002).