Diverse mutations and structural variations contribute to Notch signaling deregulation in paediatric T‐cell lymphoblastic lymphoma

Abstract

Background T‐cell lymphoblastic lymphoma (T‐LBL) is an aggressive neoplasm closely related to T‐cell acute lymphoblastic leukaemia (T‐ALL). Despite their similarities, and contrary to T‐ALL, studies on paediatric T‐LBL are scarce and, therefore, its molecular landscape has not yet been fully elucidated. Thus, the aims of this study were to characterize the genetic and molecular heterogeneity of paediatric T‐LBL and to evaluate novel molecular markers differentiating this entity from T‐ALL. Procedure Thirty‐three paediatric T‐LBL patients were analyzed using an integrated approach, including targeted next‐generation sequencing, RNA‐sequencing transcriptome analysis and copy‐number arrays. Results Copy number and mutational analyses allowed the detection of recurrent homozygous deletions of 9p/CDKN2A (78%), trisomy 20 (19%) and gains of 17q24‐q25 (16%), as well as frequent mutations of NOTCH1 (62%), followed by the BCL11B (23%), WT1 (19%) and FBXW7, PHF6 and RPL10 genes (15%, respectively). This genetic profile did not differ from that described in T‐ALL in terms of mutation incidence and global genomic complexity level, but unveiled virtually exclusive 17q25 gains and trisomy 20 in T‐LBL. Additionally, we identified novel gene fusions in paediatric T‐LBL, including NOTCH1–IKZF2, RNGTT–SNAP91 and DDX3X–MLLT10, the last being the only one previously described in T‐ALL. Moreover, clinical correlations highlighted the presence of Notch pathway alterations as a factor related to favourable outcome. Conclusions In summary, the genomic landscape of paediatric T‐LBL is similar to that observed in T‐ALL, and Notch signaling pathway deregulation remains the cornerstone in its pathogenesis, including not only mutations but fusion genes targeting NOTCH1.

T‐cell lymphoma patient harboring BCL11B mutations had favorable overall survival

“…In our TCL collective, the overall mutation rate of BCL11B was 6.4% (15/233) (Figure 1A), which was significantly lower than in the study on pediatric T‐LBL by Salmerón‐Villalobos et al. (23%) 28 . The inconsistency between this study and the published results may be due to the older age and the heterogeneity of our patients (Table 1).…”

“…In our TCL collective, the overall mutation rate of BCL11B was 6.4% (15/233) (Figure 1A), which was significantly lower than in the study on pediatric T-LBL by Salmerón-Villalobos et al (23%). 28 The inconsistency between this study and the published results may be due to the older age and the heterogeneity of our patients (Table 1). The BCL11B mutation subtypes were including p.F431V, p.P420fs, p.G847R, p.H126R, p.R648Q, p.K398N, p.L17F, p.P195L, and p.D565N, respectively, while the details of mutation sites are missing in six patients (Table 2).…”

“…T-cell lymphoblastic lymphoma (T-LBL), 28 little is known about the mutation patterns and prognostic value of BCL11B in adult TCL patients.…”

“…Although Salmerón‐Villalobos et al. described the mutation patterns of BCL11B in pediatric T‐cell lymphoblastic lymphoma (T‐LBL), 28 little is known about the mutation patterns and prognostic value of BCL11B in adult TCL patients.…”

Challenging our understanding of B‐cell lymphomagenesis and risk: Paediatric high‐grade B‐cell lymphoma, not otherwise specified with a DDX3X::MLLT10 fusion and an IGH deletion

“…Of these, the DDX3X::MLLT10 translocation and IGH deletion have not been reported in a paediatric B-cell lymphoma before. MLLT10 fusions, including with DDX3X, are found in T-cell acute lymphoblastic leukaemia (ALL), 6,7 T-cell lymphoblastic lymphoma (LBL) 8 and acute myeloid leukaemia (AML). 9 In this case, the translocation, t(10;X)(p12.31;p11.4), results in an in-frame fusion of DDX3X exons 1-4 and MLLT10 exons 18-24 (Figure 2 and Figure S3).…”