Abstract
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, TLX1hi or 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.
These data demonstrate that Notch 1 mutations are as frequent in T-LBL as T-ALL, but more frequently involve the PEST domain. They are in favour of preferential occurrence of NOTCH1 mutations in TLX1 relative to TLX3 proliferations, suggesting that evaluation of prognostic impact of Notch1 should not be performed independently of evaluation of TLX1/3 status, since TLX1 generally identifies good prognosis and TLX3 poor prognosis T-ALL. Within the 46 LALA94 adult T-ALLs, Notch1 mutated cases were of marginally superior prognosis (p=0.50); this is currently being evaluated within the ongoing adult GRAALL03 T-ALL trial.
Disclosure: No relevant conflicts of interest to declare.
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