Figure 5.
Genes and pathways associated with the activation of ID and PD signatures. (A) Epigenomic landscape of ATXN1 gene in CLL and mature B cells. The genes and genomic regions (upper) belonging to the PD or ID H3K27ac signatures and the chromatin states in 7 biologically independent CLLs, along with representative samples of normal B-cell subpopulations. No genes or peaks from the PD signatures are found within the displayed area. The median RNA-seq levels (lower) of the 7 biologically independent CLLs and 15 biologically independent normal B cells. (B) Pearson correlation coefficient between ATXN1 and NOTCH1 signaling target genes VST mRNA abundance in 5 CLL samples from the lymph nodes. P values were determined using 1-tailed tests, assuming the coefficient to follow a t distribution with 3 degrees of freedom. FDR was estimated with the Benjamini-Hochberg procedure. (C) GSEA of ES and DE1 cohorts analyzing each IGHV subtype independently. Hallmark gene sets with a normalized enrichment score (NES) absolute value >1 and adjusted P value <.1 in at least 2 analyses are depicted. GSEA results are annotated with the significance level of the P value resulting from permutation tests adjusted for multiple testing with the Benjamini-Hochberg procedure. The gene sets are ordered according to the accumulated NES across the 4 analyses, shown in the right bar. (D) Analysis of transcription factor (TF) activities in ES and DE1 cohorts, studied independently for each IGHV subtype. TFs presenting a normalized weighted mean (NWMEAN) absolute value >1.5 and P value <.01 in at least 2 analyses are displayed. The results are annotated with the significance level of the P value resulting from permutation tests. TFs are ordered according to the accumulated NWMEAN across the 4 analyses, illustrated in the right bar. (E) A panel (left) showing the association of genetic driver alterations with the balance score analyzed in the whole cohort, U-CLL and M-CLL. Point estimates with 95% confidence intervals are calculated using 2-sided t tests and controlling for FDR using the Benjamini-Hochberg method. The point estimates represent the difference between the mean balance score in individuals with CLL with and without each corresponding alteration. They are color-coded based on FDR. Genetic alterations associated with the balance score with a P value <.05 in any of the analyses are displayed. Oncoprint representation (right) of the selected genetic driver alterations. For each sample is annotated the number of genetic driver alterations, the IGHV mutational status, TTFT or right censoring time, an indicator of patient treatment after sampling, and the balance score. Samples are ordered from lower to higher balance score. The number of samples with mutations, as well as the percentage of mutated samples over the whole cohort, is shown on the right. Genetic alterations are color-coded according to their type. +FDR, 0.1; ∗∗∗∗P < .0001; ∗∗∗P < .001; ∗∗P < .01; ∗P < .05; · P < .1. Acc., accumulated; ActProm, active promoter; GCBC, germinal center B cell; H3K27me3_Repr, H3K27me3 repressed; H3K9me3_Repr, H3K9me3 repressed; Het;LowSign, Heterochromatin;Low Signal; MBC, memory B cell; NBC-PB, naïve B cell from PB; NBC-T, naïve B cell from tonsil; PCT, plasma cell from tonsil; PoisProm, poised promoter; sign., signaling; StrEnh1, Strong Enhancer 1; StrEnh2, Strong Enhancer 2; RCT, right censoring time; Txn_Elong, transcription elongation; Txn_Trans, transcription transition; Wk_Txn, weak transcription; WkEnh, weak enhancer; WkProm, weak promoter.

Genes and pathways associated with the activation of ID and PD signatures. (A) Epigenomic landscape of ATXN1 gene in CLL and mature B cells. The genes and genomic regions (upper) belonging to the PD or ID H3K27ac signatures and the chromatin states in 7 biologically independent CLLs, along with representative samples of normal B-cell subpopulations. No genes or peaks from the PD signatures are found within the displayed area. The median RNA-seq levels (lower) of the 7 biologically independent CLLs and 15 biologically independent normal B cells. (B) Pearson correlation coefficient between ATXN1 and NOTCH1 signaling target genes VST mRNA abundance in 5 CLL samples from the lymph nodes. P values were determined using 1-tailed tests, assuming the coefficient to follow a t distribution with 3 degrees of freedom. FDR was estimated with the Benjamini-Hochberg procedure. (C) GSEA of ES and DE1 cohorts analyzing each IGHV subtype independently. Hallmark gene sets with a normalized enrichment score (NES) absolute value >1 and adjusted P value <.1 in at least 2 analyses are depicted. GSEA results are annotated with the significance level of the P value resulting from permutation tests adjusted for multiple testing with the Benjamini-Hochberg procedure. The gene sets are ordered according to the accumulated NES across the 4 analyses, shown in the right bar. (D) Analysis of transcription factor (TF) activities in ES and DE1 cohorts, studied independently for each IGHV subtype. TFs presenting a normalized weighted mean (NWMEAN) absolute value >1.5 and P value <.01 in at least 2 analyses are displayed. The results are annotated with the significance level of the P value resulting from permutation tests. TFs are ordered according to the accumulated NWMEAN across the 4 analyses, illustrated in the right bar. (E) A panel (left) showing the association of genetic driver alterations with the balance score analyzed in the whole cohort, U-CLL and M-CLL. Point estimates with 95% confidence intervals are calculated using 2-sided t tests and controlling for FDR using the Benjamini-Hochberg method. The point estimates represent the difference between the mean balance score in individuals with CLL with and without each corresponding alteration. They are color-coded based on FDR. Genetic alterations associated with the balance score with a P value <.05 in any of the analyses are displayed. Oncoprint representation (right) of the selected genetic driver alterations. For each sample is annotated the number of genetic driver alterations, the IGHV mutational status, TTFT or right censoring time, an indicator of patient treatment after sampling, and the balance score. Samples are ordered from lower to higher balance score. The number of samples with mutations, as well as the percentage of mutated samples over the whole cohort, is shown on the right. Genetic alterations are color-coded according to their type. +FDR, 0.1; ∗∗∗∗P < .0001; ∗∗∗P < .001; ∗∗P < .01; ∗P < .05; · P < .1. Acc., accumulated; ActProm, active promoter; GCBC, germinal center B cell; H3K27me3_Repr, H3K27me3 repressed; H3K9me3_Repr, H3K9me3 repressed; Het;LowSign, Heterochromatin;Low Signal; MBC, memory B cell; NBC-PB, naïve B cell from PB; NBC-T, naïve B cell from tonsil; PCT, plasma cell from tonsil; PoisProm, poised promoter; sign., signaling; StrEnh1, Strong Enhancer 1; StrEnh2, Strong Enhancer 2; RCT, right censoring time; Txn_Elong, transcription elongation; Txn_Trans, transcription transition; Wk_Txn, weak transcription; WkEnh, weak enhancer; WkProm, weak promoter.

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