NOTCH1 mutation and its prognostic significance in Chinese chronic lymphocytic leukemia: a retrospective study of 317 cases

Abstract

The proto‐oncogene NOTCH1 is frequently mutated in around 10% of patients with chronic lymphocytic leukemia (CLL). This study analyzed NOTCH1 mutation status of 317 Chinese patients with CLL by Sanger sequencing. The frequencies of NOTCH1 mutation in the PEST (proline (P), glutamic acid (E), serine (S), threonine (T)‐rich protein sequence) domain and the 3′ untranslated regions (UTR) were 8.2% and 0.9%, with the most frequent mutation being c.7541_7542delCT and c.*371A>G, respectively. Clinical and biological associations were determined including NOTCH1 mutations with advanced stage (Binet stage, P = 0.010), unmutated immunoglobulin heavy‐chain variable region (IGHV) gene (P < 0.001) and trisomy 12 (+12) (P = 0.014). NOTCH1‐mutated patients had lower CD20 expression intensity than NOTCH1‐unmutated patients (P = 0.029). In addition, NOTCH1‐mutated patients had shorter overall survival (OS) (P = 0.002) and treatment‐free survival (TFS) (P = 0.002) than NOTCH1‐unmutated patients, especially for patients with NOTCH1 c.7541_7542delCT and/or c.*371A>G mutations. Patients with both mutated NOTCH1 and unmutated IGHV had shorter OS (P < 0.001) and TFS (P < 0.001) than those with unmutated NOTCH1 or mutated IGHV. These data provide a comprehensive view of the clinical relevance and prognostic impact of NOTCH1 mutations on Chinese patients with CLL.

CD markers variations in chronic lymphocytic leukemia: New insights into prognosis

“…Also, according to the relationship between UM‐IgV H with naive B‐cells and increased survival of CLL cells through activation of BCR, it appears that CLL patients with UM‐IgV H compared with CLL patients with M‐IgV H can be associated with shorter survival, resistance to therapy, and progression of disease (Mougalian & O'Brien, ; Shahjahani et al, ). In addition, studies have indicated a relationship between UM‐IgV H with poor prognostic factors such as zeta chain‐linked protein 70 (ZAP‐70) and CD38 (Figure ; Doubek et al, ; Kröber et al, ), as well as high‐risk genomic aberrations such as deletion (del) 11q, del 17p, neurogenic locus notch homolog 1 (Notch1) mutations and trisomy 12, while M‐IgV H has only been reported that has relationship with del 13q (Athanasiadou et al, ; Rigolin et al, ; Sandoval‐Sus et al, ; Zou et al, ). Considering the above statements, it can be concluded that the evaluation of IgV H mutational status in B‐cells can have an important role in predicting the pathogenesis of CLL patients.…”

Overexpression of c-Myc-dependent heterogeneous nuclear ribonucleoprotein A1 promotes proliferation and inhibits apoptosis in NOTCH1-mutated chronic lymphocytic leukemia cells

“…NOTCH1 mutation is one of the most essential molecular biological aberrations in CLL [2] . In the era of chemo-immunotherapy, patients with NOTCH1 mutation showed a poor response to treatment and had an adverse prognosis [19] . In addition, NOTCH1 and B cell receptor signals could support each other to promote the development of CLL.…”

“…[ 2 ] In the era of chemo-immunotherapy, patients with NOTCH1 mutation showed a poor response to treatment and had an adverse prognosis. [ 19 ] In addition, NOTCH1 and B cell receptor signals could support each other to promote the development of CLL. NOTCH1 mutation enhanced the expression of the B cell receptor signal by activating the NOTCH1 pathway, which in turn facilitated the translation and activation of the NOTCH1 signal.…”

Role of Notch Receptors in Hematologic Malignancies

“…Moreover, patients carrying these mutations had a more advanced stage of CLL and a higher risk of undergoing transformation into diffuse large B-cell lymphoma (DLBCL) than patients with CLL without genetic changes. Notch 1 mutations in CLL patients seem to be useful as a predictive risk factor of malignancy evolution [ 77 , 78 , 79 , 80 ].…”