O-008 Modeling and targeting MLL-PTD/RUNX1 related myelodysplastic syndromes in mice

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Results: WES identified 10 somatic mutations in our index patient. Among those, three previously reported genes in myeloid mailgnancies: BCOR, RUNX1 and STAG2. Direct sequencing of BCOR and the related BCORL1 genes in a cohort of 221 MDS patients identified additional 10 inactivating BCOR (4.5%) and five BCORL1 mutations (2.3%). Mutations were found in patients of all IPSS risk-groups and WHO subtypes. BCOR mutations were associated with RUNX1 (P=0.027). Similar frequencies for BCOR and BCORL1mutations were found in an extension cohort of 208 patients with various myeloid malignancies: 8 BCOR and 8 BCORL1 mutations (3.8% each). BCORL1 mutations were most often found in patients with AML-MRC disease (3/22=13.6%). Deep sequencing covered with a median of 6415 reads every mutation identified in 8 BCOR mutated patients. The quantified frequency of BCOR mutations affected BM cells with a range of 13.5% to 79%. With the exception of one patient, BCOR mutations never presented at the greatest frequency, which would be expected if they were involved in disease initiating events. BCOR mutations arise commonly after other mutations affecting the splicing machinery or epigenetic transcription. In univariate analysis, BCORmutationswere associated with a poor prognosis in MDS patients (Overall Survival: P=0.034, AML transformation: P=0.051). Multivariate analysis confirmed a significant inferior OS (HR: 3.3; 95%CI 1.4–8.1; P=0.008) for BCOR mutated patients. Conclusions: These data suggest that BCOR mutations are rather defining the clinical course than disease initiation and that despite their relatively low global frequency, BCOR might be considered as a key gene in risk stratification.