Distinct Consequences of BCOR and BCORL1 Mutations in Myeloid Neoplasms and Bone Marrow Failure

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.

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Journal
American Journal of Hematology
Published
2026-11-07
DOI
https://doi.org/10.1002/ajh.70542
Primary Topic
Acute Myeloid Leukemia Research
Type
article
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0.00

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article

Distinct Consequences of BCOR and BCORL1 Mutations in Myeloid Neoplasms and Bone Marrow Failure

Luca Guarnera, Carlos Bravo‐Pérez, Matteo D’Addona, Christopher Haddad et al.
2 links
American Journal of Hematology
Acute Myeloid Leukemia Research
article

Distinct Consequences of BCOR and BCORL1 Mutations in Myeloid Neoplasms and Bone Marrow Failure

Luca Guarnera, Carlos Bravo‐Pérez, Matteo D’Addona, Christopher Haddad, Valeria Visconte, Masanori Yoshida, Marcin W. Włodarski, Monika Maria Toma, Torsten Haferlach, Koichi Takahashi, Carmelo Gurnari, Arda Durmaz, Tomasz Skórski, Stephan Hütter, Serhan Ünlü, Atsushi Marumo, Mark D. Orland, Jaroslaw Pawel Maciejewski, Aashray Mandala, Xiaorong Gu, Kartik Lakhotiya, Zachary Brady, Felipe de Almeida Sartori, Akram Abushamma
article en

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.

American Journal of Hematology
University of Rome Tor Vergata (IT), Fox Chase Cancer Center (US), St. Jude Children's Research Hospital (US), Cleveland Clinic (US), The University of Texas MD Anderson Cancer Center (US), Instituto de Salud Carlos III (ES), Hospital General Universitario Morales Meseguer (ES), Munich Leukemia Laboratory (Germany) (DE), Centre for Biomedical Network Research on Rare Diseases (ES), National Center For Child Health and Development (JP), Ospedali Riuniti San Giovanni di Dio e Ruggi d'Aragona (IT), Universidad de Murcia (ES), Nippon Medical School (JP), Temple University (US)
Aplastic Anemia and MDS International Foundation, Edward P. Evans Foundation, Instituto de Salud Carlos III, National Cancer Institute
Good health and well-being
Openalex Percentile: Top 13%
Acute Myeloid Leukemia Research
DOIOpen Access PDFOpenAlex
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