Copy Number Alterations in CDKN2A/2B and MTAP Genes Are Associated With Low MEF2C Expression in T-cell Acute Lymphoblastic Leukemia

Abstract

The molecular heterogeneity of T-cell acute lymphoblastic leukemia (T-ALL) makes this disease complex. Early T-cell precursor ALL (ETP-ALL) is a recognized subtype of T-ALL associated with a high probability of induction failure with conventional therapy. Higher expression of myocyte enhancer factor 2C (MEF2C) and the absence of a biallelic deletion (ABD) are the designated markers for the ETP-ALL. Co-deletion of the contiguous genes cyclin-dependent kinase inhibitor 2A/2B (CDKN2A/2B) and the methylthioadenosine phosphorylase (MTAP) cluster, located at 9p21.3, is another common alteration in T-ALL and confers poor response to treatment. We used real-time polymerase chain reaction (PCR) analysis to assess MEF2C mRNA expression and ABD status. Copy number alterations (CNAs) in key genes previously reported to be altered in T-ALL were assessed using multiple ligation probe amplification (MLPA). We observed that CNAs in this co-deletion cluster of CDKN2A/B and MTAP genes exhibited low MEF2C expression while ABD was associated with CNA in the Abelson murine leukemia 1 (ABL1) gene. Assessment of MEF2C expression based on immunophenotype revealed that its association with CDKN2A/2B alteration is present in non-immature immunophenotype. Additionally, ABD was associated with copy number alterations of T-cell acute lymphocytic leukemia protein 1 (TAL1), myeloblastosis (MYB), and LIM domain only 2 (LMO2) genes in immature immunophenotypes. Further, STIL::TAL1 fusion was associated with low expression of MEF2C. These associations may help explain the difficulties in assessing disease heterogeneity and the prognostic importance of 9p21.3 alterations in T-ALL.