LAUSR

Background BCOR (BCL6 corepressor) is an epigenetic regulator gene involved in the specification of cell differentiation and body structure development. Recurrent somatic BCOR mutations have been identified in myelodysplastic syndrome (MDS). However, the clinical impact of BCOR mutations on MDS prognosis is controversial and the response of hypomethylating agents in MDS with BCOR mutations (BCOR MUT ) remains unknown. Results Among 676 MDS patients, 43 patients (6.4%) harbored BCOR mutations. A higher frequency of BCOR mutations (8.7%) was investigated in patients with normal chromosome, compared to 4.2% in patients with abnormal karyotype ( p  = 0.040). Compared to the BCOR WT patients, the BCOR MUT patients showed a higher ratio of refractory anemia with excess blasts subset ( p  = 0.008). The most common comutations with BCOR genes were ASXL1 ( p  = 0.002), DNMT3A ( p  = 0.114) and TET2 ( p  = 0.148). When the hierarchy of somatic mutations was analyzed, BCOR mutations were below the known initial mutations (ASXL1 or TET2) but were above U2AF1 mutations. Transformation-free survival was significantly shorter in BCOR MUT patients than that in BCOR WT patients (16 vs. 35 months; p  = 0.035). RNA-sequencing was performed in bone marrow mononuclear cells from BCOR MUT and BCOR WT patients and revealed 2030 upregulated and 772 downregulated genes. Importantly, HOXA6, HOXB7, and HOXB9 were significantly over-expressed in BCOR MUT patients, compared to BCOR WT patients. Eight of 14 BCOR MUT patients (57.1%) achieved complete remission (CR) with decitabine treatment, which was much higher than that in BCOR WT patients (28.7%, p  = 0.036). Paired sequencing results (before and after decitabine) showed three of 6 CR patients lost the mutated BCOR. The median survival of CR patients with a BCOR MUT was 40 months, which was significantly longer than that in patients with BCOR WT (20 months, p  = 0.036). Notably, prolonged survival was observed in three BCOR MUT CR patients even without any subsequent therapies. Conclusions BCOR mutations occur more frequently in CN MDS patients, predicting higher risk of leukemia transformation. BCOR MUT patients showed a better response to decitabine and achieved longer post-CR survival.