T-cell acute lymphoblastic leukemia is caused by the accumulation of multiple genetic alterations, including chromosomal rearrangements and genetic mutations. Activating mutations of NOTCH1 are present in at least 50% of T-cell ALL cases. Other mutations include loss-of-function of hematopoietic transcription factor genes, such as BCL11B, ETV6, GATA3, LEF1, RUNX1 and WT1 . Several genes involved in the regulation of epigenetics and chromatin modification are also mutated, including EZH2, SUZ12 and EED . Intracellular signaling pathways are activated by mutations, including PI3K-AKT-mTOR pathway. Several genes in the JAK-STAT pathway are also activated by mutations, such as JAK1, JAK3 and STAT5B . RAS-MAPK signaling through KRAS, NRAS and NF1 are also involved in some cases. Other genes are identified to be mutant in T-cell ALL including ribosomal biogenesis gene, such as RPL5, RPL10 and RPL11 and plant homeodomain gene PHF6 .
To determine the frequency and co-occurrence of mutations in the above pathways in childhood T-cell acute lymphoblastic leukemia, we performed targeted sequencing of 64 genes across 59 diagnostic pediatric T-cell ALL who were treated with TPOG ALL protocols 2000 and 2013 in the National Taiwan University Hospital between 2000 to 2015.
NOTCH1 mutants were identified in 40% cases (24/59) and this ratio was slightly lower than the previous reports. An additional 63 genes were mutated 1.7 % to 57% of cases (Figure). Eight target genes in the IL7R-JAK pathways were sequenced. We found that IL7R-JAK pathway genes were mutated in 23.7% of cases, with JAK3 mutations being the most frequent event in this cohort.
Targeted sequencing by Next Generation Sequence is able to profile multiple genetic alterations at the same time. Some of these genetic alterations might have therapeutic targets, such as JAK inhibitor for IL7R- JAK pathway mutant patients. These genetic alterations might help the achievements of precision medicine for childhood T-cell ALL in the future clinical trials.
No relevant conflicts of interest to declare.
Asterisk with author names denotes non-ASH members.