Distinct Consequences of BCOR and BCORL1 Mutations in Myeloid Neoplasms and Bone Marrow Failure
Year: 2026
Type: article
Study design: Observational Study
Abstract: BCOR and BCORL1 (BCOR/L1) mutations are observed in both myeloid neoplasms (MN) and bone marrow failure syndromes (BMF), but their clinical significance may differ. We analyzed 11 340 patients and identified 418 BCOR/L1-mutated patients, focusing on differences between MN and BMF. Compared with MN, BMF was associated with younger age, a higher frequency of normal karyotype, a greater proportion of missense mutations, and significantly lower variant allele frequencies (VAFs). We next compared BCOR/L1-mutated cases with wild-type cases. In MN, BCOR/L1 mutations were associated with older age, inferior survival, and a higher number of co-occurring mutations, whereas in BMF, they were associated with a higher prevalence of PNH clones. Single-cell DNA sequencing and VAF-based analysis demonstrated that BCOR/L1 mutations were usually secondary in MN but primary events in BMF. Longitudinal sequencing revealed that BCOR/L1-mutant clones often contracted or disappeared over time, even in progression, suggesting limited clonal fitness of BCOR/L1 mutations themselves; instead, progression was associated with increased mutational burden, particularly in RUNX1. Prognostically, BCOR/L1 mutations were associated with inferior survival in MN, whereas in BMF they were not associated with prognosis and tended to correlate with a favorable response to immunosuppressive therapy. RNA-sequencing analyses showed reduced BCOR/L1 expression in BMF, and BCOR knockout was associated with reduced HLA class I expression. Our findings suggest that BCOR/L1 mutations are secondary events in MN and co-occurring mutations may influence disease progression and prognosis, whereas in BMF they appear to be ancestral events acquired independently of progression to MN, potentially through immune privilege-related mechanisms.
Source: American Journal of Hematology
DOI: 10.1002/ajh.70542
Authors: Atsushi Marumo, Arda Durmaz, Christopher Haddad, Aashray Mandala, Felipe de Almeida Sartori, Akram Abushamma, Serhan Unlu, Xiaorong Gu, Zachary Brady, Matteo D'Addona, Kartik Lakhotiya, Luca Guarnera, Masanori Yoshida, Monika M. Toma, Mark D. Orland, Carlos Bravo‐Perez, Carmelo Gurnari, Koichi Takahashi, Tomasz Skorski, Stephan Hutter, Torsten Haferlach, Marcin Wlodarski, Valeria Visconte, Jaroslaw P. Maciejewski
Institutions: Cleveland Clinic, Nippon Medical School, AOU San Giovanni di Dio e Ruggi d'Aragona, University of Rome Tor Vergata, National Center For Child Health and Development, Temple University, Instituto de Salud Carlos III, Hospital General Universitario Morales Meseguer, Centre for Biomedical Network Research on Rare Diseases, Universidad de Murcia, The University of Texas MD Anderson Cancer Center, Fox Chase Cancer Center, Munich Leukemia Laboratory (Germany), St. Jude Children's Research Hospital
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $5,450
OpenAlex ID: W7225462336