Prognostic relevance of integrated genetic profiling in adult T-cell acute lymphoblastic leukemia

Abstract

Adult T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic tumor associated with poor outcome. In this study, we analyzed the prognostic relevance of genetic alterations, immunophenotypic markers, and microarray gene expression signatures in a panel of 53 adult T-ALL patients treated in the Eastern Cooperative Oncology Group E2993 clinical trial. An early immature gene expression signature, the absence of bi-allelic TCRG deletion, CD13 surface expression, heterozygous deletions of the short arm of chromosome 17, and mutations in IDH1/IDH2 and DNMT3A genes are associated with poor prognosis in this series. In contrast, expression of CD8 or CD62L, homozygous deletion of CDKN2A/CDKN2B, NOTCH1 and/or FBXW7 mutations, and mutations or deletions in the BCL11B tumor suppressor gene were associated with improved overall survival. Importantly, the prognostic relevance of CD13 expression and homozygous CDKN2A/CDKN2B deletions was restricted to cortical and mature T-ALLs. Conversely, mutations in IDH1/IDH2 and DNMT3A were specifically associated with poor outcome in early immature adult T-ALLs. This trial was registered at www.clinicaltrials.gov as #NCT00002514

Identification of fusion genes and characterization of transcriptome features in T-cell acute lymphoblastic leukemia

“…The fact that MEF2C is overexpressed in 30/37 (81.8%) cases (SI Appendix, Fig. S10) suggested a common disease mechanism (31). In addition, ETP cases had higher mutation rates of epigenetic factors, IDH2, DNMT3A, and EZH2 in particular, , imatinib (50 mg/kg) treated mice with ZA (n = 6), and dasatinib (5 mg/kg) treated mice with ZA (n = 6).…”

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

“…In contrast, the incidence of NOTCH1/FBXW7 mutations (47%) was lower in refractory/relapsed T-ALL than in the general unselected T-ALL population and these mutations were mostly found in combination with a second lesion in the pathway or different pathways, in line with their association with a favorable prognosis. [30][31][32][33] Moreover, we observed that NOTCH1/FBXW7 status could differ between matched diagnostic and relapse samples, indicating that NOTCH1/FBXW7 mutations might be secondary events in T-ALL.…”

CK2 inhibitor CX-4945 destabilizes NOTCH1 and synergizes with JQ1 against human T-acute lymphoblastic leukemic cells

“…To address this question, we analyzed publicly available databases and cross-compared the expression of CK2 subunits among subsets of developing T cells and patient T-ALL cells that are arrested at different developmental stages. 9 We found that the transcript levels of all CK2 subunits (α, α' and β) were significantly higher in patient T-ALL cells, compared to normal T cells regardless of their developmental stages ( Figure 1A and B and Online Supplementary Figure S1A). We next examined protein levels of CK2, cleaved-NOTCH1 and MYC by Western blots in a panel of primary T-ALL patient samples.…”