Mutational Landscape and Clinical Impact of SPEN Mutations in Patients with Chronic Lymphocytic Leukemia

Authors

Priyatharsini Nirmalanantham
Andrés E Quesada
Anindita Ghosh
Pei Lin
Chi Y Ok
Richard K Yang
Hong Fang
Sofia Garces
Rashmi Kanagal-Shamanna
Sanam Loghavi
Mark J Routbort
Cameron Cheng Yin
Wang Wei
Sarah Pasyar
Roland Bassett
Siba El Hussein
Nitin Jain
Jan Burger
William G Wierda
Sa Wang
Carlos Bueso-Ramos
Keyur P Patel
Leonard Jeffrey Medeiros
Fatima Zahra Jelloul

Language

English

Publication Date

11-6-2025

Journal

Cancers

DOI

10.3390/cancers17213586

PMID

41228377

PMCID

PMC12607580

PubMedCentral® Posted Date

11-6-2025

PubMedCentral® Full Text Version

Post-print

Abstract

Background/objectives: NOTCH1 is frequently mutated in chronic lymphocytic leukemia (CLL) and is a marker of poor prognosis. In addition to NOTCH1, mutations in the NOTCH1 regulatory pathway including SPEN have been described in a limited number of CLL cases and others have suggested that these mutations are also associated with adverse patient outcomes Methods: In this study, 1617 CLL cases were assessed using targeted sequencing and a 29-gene panel and the results were correlated with prognosis.

Results: SPEN mutations were detected in 48 (2.9%) CLL patients: 92.4% were deleterious (frameshift or truncating nonsense mutations) and the remaining (7.6%) were missense. Compared with SPEN wild type CLL patients, SPEN mutated patients had a statistically higher frequency of IGHV unmutated status (79.5% vs. 57.8%, p = 0.004), CD38 positivity (73.3% vs. 52.4%, p = 0.01), ZAP70 positivity (77.3% vs. 58.3%, p = 0.01) and trisomy 12 (43.5% vs. 13.7%, p < 0.001). The most common gene mutations co-occurring with SPEN mutations were as follows: NOTCH1 (43.7%), TP53 (22.9%), BIRC3 (12.5%), SF3B1 (10.4%), XPO1 (8.3%), MUC2 (6.2%), ATM (4.2%), FBXW7 (4.2%), and BTK (4.2%). Patients with SPEN mutated CLL had a significantly shorter time-to-first treatment compared to CLL patients with wild type SPEN (2.5 vs. 4.07 years, p = 0.01). The finding of shorter time-to-first treatment in SPEN mutated CLL patients was not maintained in a multivariable analysis. IGHV unmutated status, TP53 disruption, and trisomy 12 remained independently predictive of a shorter time-to-first treatment in a multivariable analysis.

Conclusions: These data show that SPEN mutations in CLL are associated with adverse prognostic impact and should be included in sequencing assays performed for the prognostic workup of CLL patients.

Keywords

chronic lymphocytic leukemia, SPEN mutations, NOTCH1 regulatory pathway

Published Open-Access

yes

Recommended Citation

Nirmalanantham, Priyatharsini; Quesada, Andrés E; Ghosh, Anindita; et al., "Mutational Landscape and Clinical Impact of SPEN Mutations in Patients with Chronic Lymphocytic Leukemia" (2025). Faculty, Staff and Student Publications. 5400.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/5400