New subtypes of oncogenic deregulation in childhood T-ALL

Large-scale whole-genome sequencing, whole-exome sequencing, and RNA-expression profiling can be used to uncover new subtypes of T-cell acute lymphoblastic leukaemia (T-ALL).

T-ALL represents approximately 15% of all newly diagnosed ALL cases in paediatric patients. T-ALL is an aggressive malignancy showing immunophenotypic diversity, including early T-cell precursor lymphoblastic leukaemia (ETP-ALL) and leukaemia of transformed thymocytes. About 20% of patients relapse or have refractory disease. Prognostic factors other than minimal residual disease are unclear [1]. Previous genetic research on patients with T-ALL has identified 8 molecular subtypes with 106 putative drivers based on gene expression clustering [2]. However, this study had a limited cohort size, excluded refractory disease, and focused on alterations in coding parts of the genome. It is now known that T-ALL gene activation is also frequently achieved by alterations in non-coding parts of the genome, e.g. MYC activation by an alteration in a distal NOTCH1 MYC enhancer [3].

Identification of genomic drivers in non-coding regions requires whole-genome sequencing and could improve the subclassification of T-ALL. Therefore, Dr Petri Pölönen (St. Jude Children's Research Hospital, TN, USA) and colleagues performed comprehensive genomic characterisation –whole-genome sequencing, whole-exome sequencing, and RNA sequencing– of all children enrolled in the AALL0434 study (NCT01295476) (n=1,313, median age 9 years old) [4].

A total of 21 T-ALL driver variants were observed in 94% of the patients combining the different genomic characterisation results, with mutations in TAL1 being the most abundant (25%). Of note, 60% of the patients had alterations in non-coding regions. Based on the genomic data, it was possible to identify 16 subtypes of T-ALL, thereby doubling the previous number of genetic subtypes. Combining the genetic characteristics with the clinical outcome of the patients, the researchers were able to show an improved survival of patients with a RPL10 R98S/C mutation over patients with RPL10 wildtype and improved survival of patients with LMO2 wildtype over LMO2 with intergenic deletion.

Based on these results, Dr Pölönen concluded that “large-scale genomic profiling of all children enrolled in the AALL0434 study has enabled the comprehensive discovery of T-ALL drivers, including candidate novel enhancer hijacking events and enhancer duplications, that are likely to result in oncogene deregulation in T-ALL.”

1. Petit A, et al. Blood 2018;131:289–300.
2. Liu Y, et al. Nat Genet. 2017;49:1211–1218.
3. Herranz D, et al. Nat Med. 2014;20:1130–1137.
4. Pölönen P, et al. Comprehensive genome characterization reveals new subtypes and mechanisms of oncogene deregulation in childhood T-ALL. Abstract S102. EHA2022 Hybrid Congress, 09–12 June.

 

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Posted on 1 July 2022