List of Supplementary Tables 1. Supplementary Table 1: Metadata and WGS/WES specifications a. Supplementary Table 1a: Metadata b. Supplementary Table 1b: WGS/WES specifications c. Supplementary Table 1c: Sex and age at CLL diagnosis 2. Supplementary Table 2: Immunoglobulin gene rearrangements and oncogenic translocations determined by IgCaller 3. Supplementary Table 3: Mutations (SNV and indels) 4. Supplementary Table 4: Copy number alterations a. Supplementary Table 4a: List of copy number alterations b. Supplementary Table 4b: Candidate driver genes affected by copy number alterations 5. Supplementary Table 5: Structural variants 6. Supplementary Table 6: DNA methylation analyses a. Supplementary Table 6a: Metadata for samples with DNA methylation data b. Supplementary Table 6b: Differentially methylated CpGs between CLL and RT 7. Supplementary Table 7: Bulk ChIP-seq of H3K27ac and transcription factor analysis a. Supplementary Table 7a: Samples and metadata b. Supplementary Table 7b: Number of changes c. Supplementary Table 7c: Richter-specific common changes d. Supplementary Table 7d: Annotated differential expression genes in Richter-specific common regions e. Supplementary Table 7e: Transcription factors (expressed in RT) f. Supplementary Table 7f: Transcription factors (differentially expressed between RT and CLL) 8. Supplementary Table 8: Bulk ATAC-seq analyses a. Supplementary Table 8a: Samples and metadata b. Supplementary Table 8b: Number of changes c. Supplementary Table 8c: Richter-specific common changes d. Supplementary Table 8d: Annotated differential expression genes in Richter-specific common regions 9. Supplementary Table 9: Coding mutations in CLL and RT 10. Supplementary Table 10: CLL and lymphoma driver genes according to previous literature a. Supplementary Table 10a: Driver gene list b. Supplementary Table 10b: Regions considered for driver genes 11. Supplementary Table 11: Bulk RNA-seq analyses a. Supplementary Table 11a: Samples and metadata b. Supplementary Table 11b: Differentially expressed genes between RT and CLL c. Supplementary Table 11c: GSEA using hallmark gene sets d. Supplementary Table 11d: GSEA using curated C2 canonical pathways e. Supplementary Table 11e: Gene Ontology (GO) analysis 12. Supplementary Table 12: SNV identified in 147 CLL samples from the ICGC cohort and in 27 CLL posttreatment samples 13. Supplementary Table 13: Extraction and assignment of genome-wide mutational signatures a. Supplementary Table 13a: Single base substitution signatures extracted by HDP b. Supplementary Table 13b: Assignment of signatures extracted by HDP c. Supplementary Table 13c: Single base substitution signatures extracted by SignatureAnalyzer d. Supplementary Table 13d: Assignment of signatures extracted by SignatureAnalyzer e. Supplementary Table 13e: Single base substitution signatures extracted by SigProfiler f. Supplementary Table 13f: Assignment of signatures extracted by SigProfiler g. Supplementary Table 13g: Single base substitution signatures extracted by sigfit h. Supplementary Table 13h: Assignment of signatures extracted by sigfit i. Supplementary Table 13i. Comparison of SBS-RT with known signatures 14. Supplementary Table 14: Extraction and assignment of mutational signatures leading to clustered mutations a. Supplementary Table 14a: Single base substitution signatures extracted by HDP b. Supplementary Table 14b: Assignment of signatures extracted by HDP c. Supplementary Table 14c: Single base substitution signatures extracted by SignatureAnalyzer d. Supplementary Table 14d: Assignment of signatures extracted by SignatureAnalyzer e. Supplementary Table 14e: Single base substitution signatures extracted by SigProfiler f. Supplementary Table 14f: Assignment of signatures extracted by SigProfiler g. Supplementary Table 14g: Single base substitution signatures extracted by sigfit h. Supplementary Table 14h: Assignment of signatures extracted by sigfit 15. Supplementary Table 15: Fitting of genome-wide mutational signatures a. Supplementary Table 15a: Fitting of mutational signatures per sample (CLL/RT cohort) b. Supplementary Table 15b: Fitting of mutational signatures per sample (147 cases from the ICGCCLL cohort) c. Supplementary Table 15c: Fitting of mutational signatures per sample (27 CLL post-treatment) d. Supplementary Table 15d: Presence of SBS-melphalan in CLL/RT samples (mSigAct) e. Supplementary Table 15e: Fitting of mutational signatures per clone 16. Supplementary Table 16: Characterization of SBS-RT a. Supplementary Table 16a: SBS-RT in coding gene mutations b. Supplementary Table 16b: Activity of mutational processes on specific chromatin states (RTprivate mutations) c. Supplementary Table 16c: Enrichment of SBS-RT on specific chromatin states (RT-specific mutations) d. Supplementary Table 16d: Activity of mutational processes on early/late replication regions (RTprivate mutations) e. Supplementary Table 16e: Enrichment of SBS-RT on early-late replication (RT-private mutations) f. Supplementary Table 16f: Replication strand bias analysis in RT- private mutations g. Supplementary Table 16g: Transcriptional strand bias analysis in RT- private mutations 17. Supplementary Table 17: Subclonal reconstruction from WGS a. Supplementary Table 17a: MCMC sampler details and tolerated errors b. Supplementary Table 17b: Clusters identified c. Supplementary Table 17c: Abundance of clusters in each time point 18. Supplementary Table 18: High-coverage, UMI-based NGS analysis a. Supplementary Table 18a: Metadata b. Supplementary Table 18b: Targeted mutations c. Supplementary Table 18c: Design of the amplicon-based NGS panel d. Supplementary Table 18d: Results 19. Supplementary Table 19: Fitting of clustered mutational signatures a. Supplementary Table 19a: Kataegis identified in the ICGC-CLL cohort b. Supplementary Table 19b: Kataegis identified in the initial CLL (#1) and RT subclones c. Supplementary Table 19c: Fitting of mutational signatures in kataegis 20. Supplementary Table 20: Single-cell DNA-seq a. Supplementary Table 20a: Samples and metadata b. Supplementary Table 20b: Studied genes c. Supplementary Table 20c: Mutations identified by scDNA-seq (from Tapestri Insights) d. Supplementary Table 20d: Allele dropout and doublet rates e. Supplementary Table 20e: Count matrices (based on infSCITE) 21. Supplementary Table 21: Characterization of immunoglobulin heavy chain gene rearrangements using high-coverage NGS a. Supplementary Table 21a: Samples and summary (Lymphotrack, DNA-based) b. Supplementary Table 21b: IGH subclones identified in case 3495 at time point 1 (Lymphotrack) c. Supplementary Table 21c: IGH subclones identified in case 3495 at time point 2 (Lymphotrack) d. Supplementary Table 21d: IGH subclones identified in case 12 at time point 1 (Lymphotrack) e. Supplementary Table 21e: Samples and results (RNA-based) 22. Supplementary Table 22: Single-cell RNA-seq: metadata, QC, clusters, and marker genes a. Supplementary Table 22a: Samples and metadata b. Supplementary Table 22b: Marker genes for clusters of case 12 c. Supplementary Table 22c: Marker genes for clusters of case 19 d. Supplementary Table 22d: Marker genes for clusters of case 63 e. Supplementary Table 22e: Marker genes for clusters of case 365 f. Supplementary Table 22f: Marker genes for clusters of case 3299 g. Supplementary Table 22g: Number of cells per time point and cluster 23. Supplementary Table 23: Single-cell RNA-seq: patient-specific DEA and GSEA a. Supplementary Table 23a: DEA for case 12 (RT vs CLL) b. Supplementary Table 23b: DEA for case 19 (RT vs CLL) c. Supplementary Table 23c: DEA for case 63 (RT vs CLL) d. Supplementary Table 23d: DEA for case 365 (RT vs CLL) e. Supplementary Table 23e: DEA for case 3299 (RT vs CLL) f. Supplementary Table 23f: GSEA for case 12 (RT vs CLL) g. Supplementary Table 23g: GSEA for case 19 (RT vs CLL) h. Supplementary Table 23h: GSEA for case 63 (RT vs CLL) i. Supplementary Table 23i: GSEA for case 365 (RT vs CLL) j. Supplementary Table 23j: GSEA for case 3299 (RT vs CLL) 24. Supplementary Table 24: Respirometry assays in intact CLL and RT cells a. Supplementary Table 24a: Samples and metadata b. Supplementary Table 24b: Measurements c. Supplementary Table 24c: Summary 25. Supplementary Table 25: BCR signaling and cell growth assays in CLL and RT cells a. Supplementary Table 25a: Samples and metadata b. Supplementary Table 25b: Mean fluorescent ratio Indo-1(violet)/Indo-1(blue) c. Supplementary Table 25c: Flow cytometry gating strategy and proliferation results

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