Abstract
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy with variable prognosis. It represents 15% of diagnosed pediatric ALL cases and has a threefold higher incidence among males. Many recurrent alterations have been identified and help define molecular subgroups of T-ALL, however the full range of events involved in driving transformation remain to be defined. Using an integrative approach combining genomic and transcriptomic data, we molecularly characterized 30 pediatric T-ALLs and identified common recurrent T-ALL targets such as FBXW7, JAK1, JAK3, PHF6, KDM6A and NOTCH1 as well as novel candidate T-ALL driver mutations including the p.R35L missense mutation in splicesome factor U2AF1 found in 3 patients and loss of function mutations in the X-linked tumor suppressor genes MED12 (frameshit mutation p.V167fs, splice site mutation g.chrX:70339329T>C, missense mutation p.R1989H) and USP9X (nonsense mutation p.Q117*). In vitro functional studies further supported the putative role of these novel T-ALL genes in driving transformation. U2AF1 p.R35L was shown to induce aberrant splicing of downstream target genes, and shRNA knockdown of MED12 and USP9X was shown to confer resistance to apoptosis following T-ALL relevant chemotherapy drug treatment in Jurkat leukemia cells. Interestingly, nearly 60% of novel candidate driver events were identified among immature T-ALL cases, highlighting the underlying genomic complexity of pediatric T-ALL, and the need for larger integrative studies to decipher the mechanisms that contribute to its various subtypes and provide opportunities to refine patient stratification and treatment.
Highlights
Acute lymphoblastic leukemia (ALL) is the most common childhood cancer, accounting for 25% of all pediatric tumors [1]
We identified common recurrent mutations in known T-cell acute lymphoblastic leukemia (T-ALL) genes (e.g. NOTCH1, PHF6, FBXW7 and JAK3) as well as novel somatic mutations in genes involved in RNA splicing (U2AF1), chromatin remodeling (KMT2C/MLL3) and of particular interest given the observed male gender bias, in X-linked genes MED12 and USP9X
We identified a rarer translocation t(1;7)(p32;q34)/TRBTAL1 in the mature T-ALL patient 849 [9] as well as the well-known t(10;11)(p12;q14) CALM-AF10 translocation in both early T-cell precursor ALL (ETP-ALL) cases 791 and 879 and a t(9;22) (q34;q11.2)/BCR-ABL in the immature T-ALL patient 748 which is very rare in T-ALL (~1%) [21, 3]
Summary
Acute lymphoblastic leukemia (ALL) is the most common childhood cancer, accounting for 25% of all pediatric tumors [1]. Despite continued refinement of childhood ALL subtype classification and improved risk-based treatment strategies, survival rates remain significantly lower among high-risk patients [2]. Pediatric T-cell ALL (T-ALL) represents 10–15% of ALL cases [3] with a quarter of the patients experiencing relapse, and lower post-relapse survival compared to the more common B-lineage ALL [1]. Despite the introduction of intensified chemotherapy protocols, very few inroads into new therapeutic approaches for these high-risk patients have been made. Recent studies [5,6,7,8] have shown that further classification of T-ALL could reveal new diagnostic markers and provide alternative targeted treatment options
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