Fig. 1: Truncating ASXL1 mutations are of prognostic significance in chronic myelomonocytic leukemia and frequently co-occur with other mutations.

a Flowchart showing the study design: An integrated multi-omics approach to discover ASXL1^MT-specific epigenetic regulatory mechanisms associated with transcriptional up-regulation. b Lollipop plot showing that all mutations in ASXL1 resulted in a frameshift preserving the HB1, ASXL, restriction endonuclease helix-turn-helix (HARE) and LXXLL motif alpha helical (ASXH) domain but not the plant homeodomain (PHD). All observed variant allele frequencies were compatible with heterozygosity. c Heatmap showing the spectrum of co-mutations, which included spliceosome components, chromatin regulators, modulators of DNA methylation, and cell signaling molecules. The prevalence of abnormal karyotypes and the burden of co-mutations were similar between ASXL1^MT and ASXL1^WT patients. d Kaplan–Meier plot showing overall survival estimates for the 375 patients with chronic myelomonocytic leukemia from which the 16 patients in this study were sampled from (median follow-up 18 months). The presence of truncating ASXL1 mutations was associated with increased all-cause mortality in this patient population (median overall survival 1.72 years, 95% CI 1.51–2.19, n = 202 versus 2.92 years, 95% CI 2.39–3.61, n = 173; HR 1.54, 95% CI 1.19–1.98, p = 0.001). This association remained consistent after adjusting for age at diagnosis, sex, and the other factors of the Mayo Molecular Risk Stratification Model (HR 1.37, 95% CI 1.05–1.78, p = 0.019, n = 375)⁸. There were no violations of the proportional hazards assumption (p = 0.113). Source data are provided as a Source Data file.