Clinical Significance of Notch1 Mutation in Chinese B-CLL Patients,

Abstract 3892

Chronic lymphocytic leukaemia (CLL) is a heterogeneous disease with variable clinical presentation and evolution, known as the most frequent leukemia in adults in Western countries. The molecular changes leading to the pathogenesis of the disease are not fully understood. Together with Notch 2, 3, 4, Notch 1 constitute a family of heterodimeric transmembrane proteins and encodes a class I transmembrane protein functioning as a ligand-activated transcription factor and playing an important role in cell differentiation, proliferation, and apoptosis. An oncogenic role for Notch signaling has well established in T-acute lymphoblastic leukemia (T-ALL). It has been reported that up to 60% of T-ALL have activated gain-of-function mutations in Notch1 gene. Nevertheless, few Notch1 mutations have been reported in CLL.

Recently, using whole-genome sequencing, Puente et al identified 46 somatic mutations that potentially affect gene functions in CLL, further analysis of these mutations identified that Notch 1 is recurrently mutated. Through functional and clinical analyses, it is confirmed that Notch 1 mutation is oncogenic change that contribute to the clinical evolution of CLL. Mauro et al eported that 2/43(4.6%) B-CLL patients had Notch 1 activating mutations and both had unmutated IGHV, ZAP-70 positive and had a very poor prognosis. Giulia et al reported 10/120 (8.3%) patients at CLL diagnosis harbor Notch 1 mutation, and these patients also had higher incidence of unmutated IGHV, ZAP-70 positive and poor prognosis when compared with CLL patients harboring wild-type Notch 1. To date, there is no study on Notch 1 mutation in Chinese patients with CLL, the aim of this study was to investigate Notch 1 mutation in Chinese patients with CLL, to confirm whether it could be a prognostic marker in Chinese CLL cohort. In this study, Exon 26, 27 and 34 of Notch1 were successfully investigated by polymerase chain reaction (PCR) and sequence screening in 100 CLL patients and the results were compared with other factors including clinical stages, IGHV gene status and ZAP-70 expression. PEST domain mutation locating in exon 34 of Notch1 was found in 8/100(8.0%) CLL patients while there were no mutations of other three domains including HD-N, HD-C and TAD. The mutation occurs in 5 males, 3 females and median age at diagnosis was 70 years (range 51–83 years). According to the Binet staging system, 6/7 (85.7%) patients were in stage B+C, 1/7 (14.3%) patients were in stage A (p <0.01) and one patient did not got disease staging at diagnosis. 4/6(66.7%) patients carried unmutated IGHV genes and 3/7 (42.9%) CD38 and 2/7 (28.6%) ZAP-70 were positive. Chromosomal anomalies were assessed by fluorescent in situ hybridization (FISH) on 7 of the 8 Notch1 mutated patients. Of which, two patients presented with del13q14 and one with a normal FISH pattern, moreover, one presented with del17p13 and 14q32 rearrangement, one with trisomy 12 and del17p13, one with del17p13 and del11q22, one with del17p13 and del13q14. Time-to-treatment (TTT) was shorter in patients with Notch1 mutation than patients with wild-type Notch1 (4 vs. 12 months). One patient with Notch1 mutation had an invasive progression and died. Results also show that Patients with Notch1 mutation had higher rates of unmutated IGHV genes (66.7% vs. 29.1%), older ages (70 years vs. 60 years), more progressive stage (Binet B+C 85.7% vs. 45.9%) when compared with those with wild-type Notch1. The study showed that patients with Notch1 mutation indicate poor prognosis and the status of mutation may be a novel prognostic factors in CLL.