Notch1 Mutations In Adult T Lymphoblastic Lymphoma And T-All.

Notch1 is recognised to be involved in human T-ALL oncogenesis, initially by implication of its intracellular domain in the rare translocation t(7;9) and more recently with the description of mutations in NOTCH1 exons coding the heterodimerisation (HD) +/− PEST domains in 50% of T-ALL. Favorable prognosis impact of Notch1 mutations has been shown in pediatric patients. Little data is available regarding Notch mutations in adult T-ALL, and even less in adult T Lymphoblastic lymphoma (T-LBL). We have therefore searched for Notch1 mutations in adult T-ALL and T-LBL, all of which have undergone comparable, TCR and oncogene based classification (TLX1/3, SIL-TAL1, CALM-AF10, LMO1/2, TAL1 and LYL1). We searched for mutations in exons 26, 27 and 34 by direct sequencing in 46 T-ALL (median age 27,5y. range 16–54; 6 < 18y) and 32 T-LL (median 31y., range 16–70y.; 3 < 18y.). Notch1 mutations were identified in 22/46 (48%) of T-ALL and 16/32 (50%) of T-LBL. The type of mutations differed, insofar as HD only mutations were seen in 16/22 (73%) of mutated T-ALL but only 4/16 (25%) of mutated T-LL whereas PEST only mutations were seen in 2/22 (9%) T-ALL compared to 8/16 (50%) of T-LBL. The incidence of HD and PEST mutations was identical in T-ALL (4/16; 25%) and T-LBL (6/22; 27%). Combining T-ALL and T-LBL, TLX1hior TLX3 expression was seen in 7/71 (10%) and 5/71 (7%) cases respectively. Notch1 mutations were seen in 7/7 TLX1+cases but only 1/5 TLX3 (p=0.004). With respect to stage of maturation arrest, Notch mutations in T-ALL were relatively rare in mature TCR+ cases (2/15 vs. 20/31 p=0.001), whereas they were found at all stages of maturation arrest in T-LBL.