BCORL1 – Acute Myeloid Leukemia

BCL6 corepressor‐like 1 (BCORL1) encodes a transcriptional corepressor that interacts with the noncanonical PRC1.1 complex to regulate chromatin states. Somatic BCORL1 mutations have emerged as recurrent events in acute myeloid leukemia (AML), implicating BCORL1 as a novel tumor suppressor and potential biomarker in AML pathogenesis.

Multiple cohorts have identified BCORL1 mutations in adult and pediatric AML. In an unselected adult AML cohort, BCORL1 alterations occurred in 6% of 173 patients (PMID:21989985), while a large intensively treated AML study found BCORL1 variants in 3.5% of 1,529 cases (PMID:33926021). In pediatric AML, BCORL1 was mutated in 7 of 182 patients (3.4%) within the epigenetic regulator category (PMID:27470916). These independent observations across adult and pediatric populations support a strong gene–disease association.

BCORL1 mutations in AML are predominantly inactivating, including nonsense, frameshift, and splice‐site changes consistent with loss of function. The variant spectrum encompasses c.2314C>T (p.Gln772Ter) and other truncating alleles, underscoring a haploinsufficiency mechanism in leukemogenesis. All events are somatic and were absent in remission samples, confirming their role as acquired drivers.

Functional studies demonstrate that BCORL1 mutations disrupt PRC1.1 complex assembly, unlinking the RING1/PCGF1 enzymatic core from chromatin‐targeting modules. This defect leads to loss of H3K36me2 demethylation and persistent activation of oncogenic target loci, driving treatment resistance in AML cell lines and primary samples (PMID:35015684). Such mechanistic insights validate BCORL1’s tumor suppressor role.

Clinically, BCORL1 mutations co‐occur with DNMT3A and RUNX1 variants and are enriched in intermediate‐risk ELN categories. Loss‐of‐function BCORL1 alterations are associated with shorter event‐free and relapse‐free survival, suggesting prognostic utility. Moreover, the persistence of BCORL1‐mutant clones post‐chemotherapy highlights its relevance for minimal residual disease monitoring.

In summary, somatic BCORL1 mutations are a recurrent and functionally impactful subgroup in AML, with implications for diagnosis, prognosis, and therapeutic targeting. Incorporation of BCORL1 sequencing into AML panels can improve risk stratification and guide epigenetic therapy trials.

References

• Blood • 2011 • Somatic mutations in the transcriptional corepressor gene BCORL1 in adult acute myelogenous leukemia PMID:21989985
• British journal of haematology • 2016 • Whole-exome sequencing reveals the spectrum of gene mutations and the clonal evolution patterns in paediatric acute myeloid leukaemia PMID:27470916
• Cancers • 2021 • Loss-of-Function Mutations of BCOR Are an Independent Marker of Adverse Outcomes in Intensively Treated Patients with Acute Myeloid Leukemia PMID:33926021
• Blood cancer discovery • 2022 • BCOR and BCORL1 Mutations Drive Epigenetic Reprogramming and Oncogenic Signaling by Unlinking PRC1.1 from Target Genes PMID:35015684

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