<i><scp>NOTCH</scp>1</i> mutational status in chronic lymphocytic leukaemia: clinical relevance of subclonal mutations and mutation types

D'Agaro, Tiziana; Bittolo, Tamara; Bravin, Vanessa; Bo, Michele Dal; Pozzo, Federico; Bulian, Pietro; Rossi, Francesca Maria; Zucchetto, Antonella; Degan, Massimo; D’Arena, Giovanni; Chiarenza, Annalisa; Zaja, Francesco; Pozzato, Gabriele; Raimondo, Francesco Di; Rossi, Davide; Gaïdano, Gianluca; Poeta, Giovanni Del; Gattei, Valter; Bomben, Riccardo

doi:10.1111/bjh.14843

Cited by 22 publications

(33 citation statements)

References 11 publications

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“…The effects of different types of NOTCH1 mutations on prognosis were reported by D'Agaro et al. . Although Xia et al.…”

Section: Introductionmentioning

confidence: 88%

“…It has been reported that NOTCH1 abnormality represented a poor prognostic factor in CLL on both treatment-free survival (TFS) and overall survival (OS) [5,16,17]. The effects of different types of NOTCH1 mutations on prognosis were reported by D'Agaro et al [24]. Although Xia et al [25] and Wu et al [26] partly investigated NOTCH1 mutations in Chinese with CLL, so far, there has been no systemic study.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2018

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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.

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“…The effects of different types of NOTCH1 mutations on prognosis were reported by D'Agaro et al. . Although Xia et al.…”

Section: Introductionmentioning

confidence: 88%

Section: Introductionmentioning

confidence: 99%

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

et al. 2018

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“…NGS studies in CLL revealed several mutations other than the hotspot dinucleotide deletion targeting the function of the C-terminal PEST domain ( 8 , 21 , 31 – 34 ) (Table 1 ; Figure 3 ). These genetic alterations include frameshift mutations or truncations that affect different nucleotides in exon 34 and occur with lower frequency than that of the canonical delCT mutation (12.5%).…”

Section: Notch1 Mutational Status In Cllmentioning

confidence: 99%

“…Similar alterations have been shown to be leukemogenic in T-ALL, suggesting a specific function in CLL. In addition, PEST domain mutants include a small number of missense mutations ( 34 ), some of which are reported in the single-nucleotide polymorphism database, suggesting their limited role in CLL. The TAD and ANK domains are targets of frameshift non-sense mutations in 1.9 and 0.4% of CLL, and generally determine a premature stop codon.…”

Section: Notch1 Mutational Status In Cllmentioning

confidence: 99%

NOTCH1 Aberrations in Chronic Lymphocytic Leukemia

et al. 2018

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Chronic lymphocytic leukemia (CLL) is an incurable B-cell neoplasm characterized by highly variable clinical outcomes. In recent years, genomic and molecular studies revealed a remarkable heterogeneity in CLL, which mirrored the clinical diversity of this disease. These studies profoundly enhanced our understanding of leukemia cell biology and led to the identification of new biomarkers with potential prognostic and therapeutic significance. Accumulating evidence indicates a key role of deregulated NOTCH1 signaling and NOTCH1 mutations in CLL. This review highlights recent discoveries that improve our understanding of the pathophysiological NOTCH1 signaling in CLL and the clinical impact of NOTCH1 mutations in retrospective and prospective trials. In addition, we discuss the rationale for a therapeutic strategy aiming at inhibiting NOTCH1 signaling in CLL, along with an overview on the currently available NOTCH1-directed approaches.

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“…Further insight into the molecular biology of CLL has identified the novel therapeutic targets that are currently being explored. NOTCH1 for example has emerged as a commonly mutated gene in CLL that is associated with poor prognosis, including shorter time to first treatment, risk of Richter's transformation, and OS . NOTCH inhibitors have recently entered the clinic, though their role in patients with NOTCH mutated CLL remains to be determined.…”

Section: Emerging Therapeutic Targetsmentioning

confidence: 99%

Advances in drug‐based therapies in chronic lymphocytic leukemia and future prospects

Crombie

Brown

2019

Adv Cell Gene Ther

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Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the western world, with over 20 000 new cases diagnosed in the United States each year. 1 It is characterized by a clonal expansion of CD5 positive B cells within the blood, bone marrow, lymph nodes, and spleen. 2 The disease course for patients with CLL is markedly varied with a subset of patients experiencing indolent disease that does not require therapy for decades, while others experience more rapidly progressive disease despite the multiple lines of therapy. A deeper insight into the biology of CLL has identified factors that contribute to disease heterogeneity and has paved the way for a pharmacologic revolution, with the development of a variety of highly effective and well-tolerated novel, targeted agents. As a result, using prognostic information to guide treatment selection has become a priority, in order to identify patients for whom conventional chemoimmunotherapy (CIT) remains appropriate and those for whom novel treatment approaches may provide improved outcomes. AbstractChronic lymphocytic leukemia (CLL) has experienced a revolution over the past few decades with a marked expansion in therapeutic options and improvement in outcomes. This success can be attributed to an improved understanding of the molecular and genetic underpinnings of disease pathogenesis and the emergence of a variety of effective, well-tolerated, targeted therapies. The field is now continuing to evolve with an improved understanding of prognostic and predictive biomarkers of response, exploration of novel combination strategies with the goal of inducing deeper and more durable remissions, and the development of next-generation and immunebased agents. Here, we review the recent advances in CLL therapy as well as the novel therapeutic innovations that are likely to contribute to the rapidly evolving treatment paradigms in this disease. K E Y W O R D Sacalabrutinib, chronic lymphocytic leukemia, CLL, duvelisib, ibrutinib, targeted therapy, venetoclax

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NOTCH1 mutational status in chronic lymphocytic leukaemia: clinical relevance of subclonal mutations and mutation types

Cited by 22 publications

References 11 publications

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

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

NOTCH1 Aberrations in Chronic Lymphocytic Leukemia

Advances in drug‐based therapies in chronic lymphocytic leukemia and future prospects

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