Prognostic implications of NOTCH1 and FBXW7 mutations in adult acute T-lymphoblastic leukemia

Abstract

BackgroundNOTCH1 mutations have been associated with a favorable outcome in pediatric acute Tlymphoblastic leukemia. However, the results of studies on the prognostic significance of NOTCH1 mutations in adult T-lymphoblastic leukemia remain controversial. Design and MethodsHere we have investigated the prognostic impact of mutations in the NOTCH1 pathway, in particular, the NOTCH1 and FBXW7 genes, in a large cohort of adult patients with Tlymphoblastic leukemia (n=126). We determined the occurrence of mutations in NOTCH1 and FBXW7 by DNA amplification and direct sequencing of polymerase chain reaction products. ResultsMutations were identified in 57% and 12% of the NOTCH1 and FBXW7 genes, respectively. The characteristics of patients carrying NOTCH1 and/or FBXW7 (NOTCH1-FBXW7) mutations were similar to those with wild-type genes. Patients with NOTCH1-FBXW7 mutations more often showed a thymic immunophenotype (p=0.001). In the overall cohort, no significant differences were seen in the complete remission or event-free survival rates between patients with mutated or wild-type NOTCH1-FBXW7 (p=0.39). ConclusionsNOTCH1 and FBXW7 mutations were not predictive of outcome in the overall cohort of adult patients with T-lymphoblastic leukemia, but there was a trend towards a favorable prognostic impact of NOTCH1-FBXW7 mutations in the small subgroup of patients with low-risk ERG/BAALC expression status. Our findings further confirm the high frequency of NOTCH1 mutations in adult T-lymphoblastic leukemia.Key words: acute T-lymphoblastic leukemia, NOTCH1, FBXW7, mutations. T-lymphoblastic leukemia. Haematologica 2009;94:1383-1390. doi:10.3324/haematol.2008 This is an open-access paper. Citation: Baldus CD, Thibaut J, Goekbuget N, Stroux A, Schlee C, Mossner M, Burmeister T, Schwartz S, Bloomfield CD, Hoelzer D, Thiel E, and Hofmann W-K. Prognostic implications of NOTCH1 and FBXW7 mutations in adult acute Prognostic implications of NOTCH1 and FBXW7 mutations in adult acute T-lymphoblastic leukemia

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

“…[42][43][44][45] Similarly, controversial results on the prognostic effect of NOTCH activation have been obtained in adult T-ALL. [46][47][48][49] These inconsistent results might at least in part be explained by the prognostic relevance of functional interplay between specific genetic lesions in T-ALL, as recently shown for NOTCH1 activation and inactivation of PTEN in children with T-ALL treated according to Berlin-Frankfurt-Munster study protocols. 50 In our study, both univariate and multivariate analyses revealed that patients whose leukemias showed mutations in NOTCH1 and/or FBXW7 had a favorable outcome.…”

Initial Diagnostic Workup of Acute Leukemia: Guideline From the College of American Pathologists and the American Society of Hematology

“…Some studies suggest an improved early response to therapy and prognosis in these patients, although others lack prognostic 21,329 although a trend toward improved EFS was seen in one (P ¼ .10). 21 In pediatric T-ALL, one study identified an improved early response to therapy (P , .01), decreased early (FBXW7 and/or NOTCH1) and late MRD (NOTCH1, P , .01), and improved EFS (NOTCH1; P ¼ .01).…”

Poor Response to Standard Chemotherapy in Early T-precursor (ETP)-ALL: A Subtype of T-ALL Associated with Unfavourable Outcome: A Brief Report

“…Most recently, for the group of ETP-ALL a mutational spectrum similar to acute myeloid leukemia (AML) was observed [6,7].ETP-ALL patients show less frequent NOTCH 1 mutations (15 %) [8,9] and a high rate of FLT-3 mutations (35 %). Even among ETP-ALL patients, patients with a FLT3 mutation show a distinct immunophenotype with positivity for CD117, CD34, CD13 and CD2.…”