T‐cell lymphoblastic lymphoma shows differences and similarities with T‐cell acute lymphoblastic leukemia by genomic and gene expression analyses

Abstract

T-cell acute lymphoblastic leukemia (T-ALL) and lymphoma (T-LBL) share common morphological and immunophenotypic features and are treated with similar therapeutic approaches. Nonetheless, they show distinct clinical presentations, suggesting that they may represent two different biological entities. To investigate the genetic characteristics of T-LBL and T-ALL, we used genomic and transcriptional profiling approaches. Genome-wide gene expression profiling, performed on 20 T-LBL and 10 T-ALL diagnostic specimens, revealed that the two malignancies shared a large fraction of their transcriptional profile while a subset of genes appeared to be differentially expressed in T-LBL versus T-ALL. This signature included genes involved in chemotactic responses and angiogenesis, which may play a role in tumor cell localization. Genome-wide copy number alteration analysis was performed on a subset of the samples analyzed by gene expression profiling and detected 41 recurrently altered genetic loci. Although most aberrations were found in both entities, several were selectively identified in T-LBL or T-ALL. In addition, NOTCH1 mutational status was found to correlate with a subset of genetic aberrations. Taken together, these results suggest that T-LBL and T-ALL are indeed two distinct diseases with unique transcriptional and genetic characteristics.

Incidence and prognostic relevance of genetic variations in T-cell lymphoblastic lymphoma in childhood and adolescence

“…11,17,24,25 This study, which included 116 evaluable patients, strengthened the input to that field. The detected mutations in the current study were mainly either mismatch mutations or small inframe deletions/insertions in the HD domain and nonsense or frameshift mutations in the PEST domain of NOTCH1, as well as mismatch mutations affecting 3 essential positions within the canonical binding pocket of FBXW7.…”

“…[9][10][11][12][13][14][15][16][17][18][19] T-LBL and T-ALL are often considered to be closely related or 2 manifestations of 1 disease; however, recent publications provide evidence for molecular differences between them. 24,27,[38][39][40][41][42] Among others, differences in the common deleted region and, most likely because of that, in the prognostic effect of chromosome 6q alterations between T-ALL and T-LBL are described.…”

“…This fits with the common understanding that the NOTCH1 pathway is responsible for early T-cell development, which is disturbed both in T-ALL and T-LBL. Several studies indicate a favorable prognosis for patients with T-ALL with the NOTCH1 mutation compared with nonmutated patients [9][10][11][12][13][14][15][16][17][18][19] (supplemental Table 1). However, available data on T-ALL are not absolutely consistent, as the effect of the mutation might depend on the applied treatment.…”

“…In recent studies, activating mutations of NOTCH1 and/or FBXW7 (N/F pos ) have been observed in about 50% of pediatric patients with T-cell lymphoblastic leukemia (T-ALL; for a complete overview of publications dealing with this topic, see supplemental Table 1 on the Blood website). [9][10][11][12][13][14][15][16][17][18][19] The evolutionary highly conserved NOTCH1 signaling pathway is involved in the regulation of many cellular processes; for example, early T-cell development. 20,21 The transmembrane protein NOTCH1 is activated by the contact of NOTCH1-ligands (Delta-like 1-4, Jagged1, or Jagged2), which trigger the proteolytic cleavages releasing the protein's active part, intracellular NOTCH1 (ICN1).…”

“…11,17,24,25 Other genetic markers that might be of prognostic relevance are alterations of chromosome 6q. In previous studies, we could show in a limited test cohort of patients that loss of heterozygosity (LOH) at chromosome 6q14-24 (LOH6q) is associated with a significantly increased risk for relapse.…”