T-cell acute lymphoblastic leukemia (T-ALL) is a clonal malignancy of immature T cells, accounting for 15% of pediatric ALL and 25% of adult ALL. Significant therapeutic progress has been made in pediatric T-ALL, while the outcome remains poor in adult T-ALL. Therefore, it is important to further characterize the molecular pathogenesis of T-ALL. Recently, the next-generation sequencing approach allowed systematic identification of molecular markers in pediatric T-ALL.

Here, by performing RNA-sequencing and other genomic analysis, we investigated genomic landscape in 130 T-ALL cases. 36 distinct gene fusions were identified, including 18 novel ones. Four types of gene abnormalities were identified among novel fusions. Of note, newly discovered ZBTB16-ABL1 and TRA-SALL2 fusions, and the involvement of NKX2-1, were recurrent events. Functional studies revealed the recurrent ZBTB16-ABL1 fusion as a leukemogenic driver. Among 48 genes with mutation rates>3%, 6 were newly found in T-ALL. Moreover, aberrant mRNA isoform of SLC17A9 gene was found in majority of cases with high expression of TAL1 . Although most fusions were mutually exclusive, they co-existed with mutations. These genetic abnormalities were correlated to deregulated gene expression markers in three transcriptome-based subgroups. The G1 group mainly harbored TLX1 or TLX3 high expression, and over-expression of HOXA gene family. The transcriptome landscape of G2 group was closely associated with NUP family genes-containing fusions. The transcriptional factors important for early hematopoiesis were also found highly expressed in this group. Notably, 91.7% of our ETP cases were clustered in G2 group. With regard to G3, all patients with STIL-TAL1 and LMO1/2-TRA were located in this group, as cases with variant fusions involving TAL1 or STIL did. The genes with transcriptional aberration related to STIL-TAL1 were found over-expressed in most cases of G3 group. Finally, we compared genomic landscapes between adult and pediatric T-ALL patients. The types of fusions seemed more diverse in children than in adults, and the mutation rates in the genes of signaling pathways and epigenetic factors, both of which been frequently seen in ETP-ALL, were much higher in adults than in children. Our data suggest that the two T-ALL age groups might represent distinct disease entities, which could explain, at least in part, their distinct clinical outcomes. This study shed new lights on the leukemogenesis of T-ALL.


No relevant conflicts of interest to declare.

Author notes


Asterisk with author names denotes non-ASH members.