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

1 Charité, University Hospital Berlin, Campus Benjamin Franklin, Department of Hematology and Oncology, Berlin, Germany 2 University Frankfurt am Main, Department of Hematology and Oncology, Frankfurt/Main, Germany 3 Charité, University Hospital Berlin, Campus Benjamin Franklin, Department of Biostatistics and Clinical Epidemiology, Berlin, Germany 4 The Ohio State University, Comprehensive Cancer Center, Columbus, OH, USA Correspondence: Claudia D Baldus, M.D., Charité, University Hospital Berlin, Campus Benjamin Franklin, Department of Hematology and Oncology, Hindenburgdamm 30 12203 Berlin, Germany. E-mail: claudia.baldus{at}charite.de Background: NOTCH1 mutations have been associated with a favorable outcome in pediatric acute T-lymphoblastic leukemia. However, the results of studies on the prognostic significance of NOTCH1 mutations in adult T-lymphoblastic leukemia remain controversial. Design and Methods: Here 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 T-lymphoblastic leukemia (n=126). We determined the occurrence of mutations in NOTCH1 and FBXW7 by DNA amplification and direct sequencing of polymerase chain reaction products. Results: Mutations 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). Conclusions: NOTCH1 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. Related Article Mutations of NOTCH1 , FBXW7 , and prognosis in T-lineage acute lymphoblastic leukemia Charles G. Mullighan Haematologica 2009 94: 1338-1340. [Full Text] [PDF]