RNA sequencing unravels the genetics of refractory/relapsed T-cell acute lymphoblastic leukemia. Prognostic and therapeutic implications

Abstract

Despite therapeutic improvements, a sizable number of patients with T-cell acute lymphoblastic leukemia still have a poor outcome. To unravel the genomic background associated with refractoriness, we evaluated the transcriptome of 19 cases of refractory/early relapsed T-cell acute lymphoblastic leukemia (discovery cohort) by performing RNA-sequencing on diagnostic material. The incidence and prognostic impact of the most frequently mutated pathways were validated by Sanger sequencing on genomic DNA from diagnostic samples of an independent cohort of 49 cases (validation cohort), including refractory, relapsed and responsive cases. Combined gene expression and fusion transcript analyses in the discovery cohort revealed the presence of known oncogenes and identified novel rearrangements inducing overexpression, as well as inactivation of tumor suppressor genes. Mutation analysis identified JAK/STAT and RAS/PTEN as the most commonly disrupted pathways in patients with chemorefractory disease or early relapse, frequently in association with NOTCH1/FBXW7 mutations. The analysis on the validation cohort documented a significantly higher risk of relapse, inferior overall survival, disease-free survival and event-free survival in patients with JAK/STAT or RAS/PTEN alterations. Conversely, a significantly better survival was observed in patients harboring only NOTCH1/FBXW7 mutations: this favorable prognostic effect was abrogated by the presence of concomitant mutations. Preliminary in vitro assays on primary cells demonstrated sensitivity to specific inhibitors. These data document the negative prognostic impact of JAK/STAT and RAS/PTEN mutations in T-cell acute lymphoblastic leukemia and suggest the potential clinical application of JAK and PI3K/mTOR inhibitors in patients harboring mutations in these pathways.

NOTCH1 mutation, TP53 alteration and myeloid antigen expression predict outcome heterogeneity in children with first relapse of T-cell acute lymphoblastic leukemia

“…Therefore, this small number of patients prevented us from studying a prognostic impact of NRAS/KRAS and PTEN mutations within the favorable NOTCH1 mutant group that was described previously in primary adult T-ALL. 5,17 However, it is worth noting that NRAS/KRAS and PTEN mutations were absent from the most favorable NOTCH1/FBXW7 double mutant group of T-ALL relapse patients (Figure 1). TP53 mutation and/or deletion was associated with exceptionally poor outcome in relapsed T-ALL in this study, as all patients suffered a second event and died (pEFS: 0.00±0.00 vs. 0.261±0.052; P=0.051; Figure 2B).…”

Epigenetic Function of TET Family, 5-Methylcytosine, and 5-Hydroxymethylcytosine in Hematologic Malignancies

“…In jawed vertebrates, triplication of a common ancestral TET gene led to three different TET paralogs, and a subsequent chromosomal inversion split TET2 gene into two segments encoding catalytic domain and CXXC domain, respectively [43, 45, 46]. Thus, the ancestral CXXC domain of TET2 is now separately encoded by a neighboring gene named IDAX (also known as CXXC4).…”

CXCR4 allows T cell acute lymphoblastic leukemia to escape from JAK1/2 and BCL2 inhibition through CNS infiltration

“…Development of targeted therapies that inhibit pathways exploited by T-ALL to augment proliferation and survival may improve outcomes while also minimizing systemic toxicity. Prior studies involving RNA or whole genome sequencing of T-ALL samples identified the JAK/STAT pathway (32)(33)(34) and the BCL2 pathway (15) as dysregulated in these leukemias.…”