Figure 4.
NRF1-dependent transcriptional signature correlates with poor survival in multiple myeloma. (A) Schematic representation of the workflow used to identify genes that are regulated by NRF1 and show increased (n = 117), decreased (n = 12), or constant (n = 222) expression during disease progression. (B) Box plot reporting the normalized expression levels (TPM) of NRF1-regulated genes showing increased activity as the disease progresses through stages ISS I, ISS II, and ISS III. Paired significance between stages was computed using the Wilcoxon test (∗P < .05; ∗∗∗∗P < .0001). (C) Box plot depicting the TPM values of the 119 genes associated with NRF1 in Kms18 and Kms27 under siControl (violet) and siNRF1 (yellow). Wilcoxon rank-sum test (∗∗∗P < .001). (D) Box plot depicting the TPM values of the 119 genes associated with NRF1 in MGUS (violet, n = 9) and NDMM (yellow, n = 12). Wilcoxon rank-sum test (∗∗∗P < .001). (E) Heat map depicting the unsupervised clustering of the normalized scaled expression (TPM) of the highly correlated NRF1-regulated genes signature (n = 119) in the MMRF-CoMMpass cohort. Patients with MM were assigned into 2 clusters: C1 characterized by the low expression of the gene signature (blue) and C2 with high expression levels (orange). The top panel displays clinical features (ISS stage: red, ISS III; orange, ISS II; light orange, ISS I), key MM-associated mutations and translocations (dark gray, present; light gray, absent), and molecular features (NRF1 expression levels). NRF1 expression levels were categorized into 5 groups based on quantile thresholds derived from its expression distribution in the cohort (low ≤ Q20; Q20 < low_medium ≤ Q40; Q40 < medium ≥ Q60; Q60 < high_medium ≤ Q80; and high < 80). (F) Donut plots showing the percentage of patients with MM per ISS stage in C1 (left) and C2 (right) from panel E. (G) Kaplan-Meier survival analysis comparing the OS of patients with MM from the MMRF-CoMMpass cohort grouped into 2 clusters, C1 (gray) and C2 (dark green), from the panel E. C2 exhibits significantly worse survival compared with C1 (P < .0001). In the top panel, x-axis represents months, and the y-axis shows the probability of survival for each patient. The table below the plot indicates the number of patients at risk over time in each cluster. (H) Kaplan-Meier survival analysis comparing the OS of patients with MM from the MMRF-CoMMpass with patients grouped into C1 and C2 and stratified by ISS stages I, II, and III. C2 consistently shows worse survival outcomes across all ISS stages, with P values of 0.071 (ISS I), <0.0001 (ISS II), and 0.038 (ISS III). The tables below each plot indicate the number of patients at risk over time in each cluster and stage.

NRF1-dependent transcriptional signature correlates with poor survival in multiple myeloma. (A) Schematic representation of the workflow used to identify genes that are regulated by NRF1 and show increased (n = 117), decreased (n = 12), or constant (n = 222) expression during disease progression. (B) Box plot reporting the normalized expression levels (TPM) of NRF1-regulated genes showing increased activity as the disease progresses through stages ISS I, ISS II, and ISS III. Paired significance between stages was computed using the Wilcoxon test (∗P < .05; ∗∗∗∗P < .0001). (C) Box plot depicting the TPM values of the 119 genes associated with NRF1 in Kms18 and Kms27 under siControl (violet) and siNRF1 (yellow). Wilcoxon rank-sum test (∗∗∗P < .001). (D) Box plot depicting the TPM values of the 119 genes associated with NRF1 in MGUS (violet, n = 9) and NDMM (yellow, n = 12). Wilcoxon rank-sum test (∗∗∗P < .001). (E) Heat map depicting the unsupervised clustering of the normalized scaled expression (TPM) of the highly correlated NRF1-regulated genes signature (n = 119) in the MMRF-CoMMpass cohort. Patients with MM were assigned into 2 clusters: C1 characterized by the low expression of the gene signature (blue) and C2 with high expression levels (orange). The top panel displays clinical features (ISS stage: red, ISS III; orange, ISS II; light orange, ISS I), key MM-associated mutations and translocations (dark gray, present; light gray, absent), and molecular features (NRF1 expression levels). NRF1 expression levels were categorized into 5 groups based on quantile thresholds derived from its expression distribution in the cohort (low ≤ Q20; Q20 < low_medium ≤ Q40; Q40 < medium ≥ Q60; Q60 < high_medium ≤ Q80; and high < 80). (F) Donut plots showing the percentage of patients with MM per ISS stage in C1 (left) and C2 (right) from panel E. (G) Kaplan-Meier survival analysis comparing the OS of patients with MM from the MMRF-CoMMpass cohort grouped into 2 clusters, C1 (gray) and C2 (dark green), from the panel E. C2 exhibits significantly worse survival compared with C1 (P < .0001). In the top panel, x-axis represents months, and the y-axis shows the probability of survival for each patient. The table below the plot indicates the number of patients at risk over time in each cluster. (H) Kaplan-Meier survival analysis comparing the OS of patients with MM from the MMRF-CoMMpass with patients grouped into C1 and C2 and stratified by ISS stages I, II, and III. C2 consistently shows worse survival outcomes across all ISS stages, with P values of 0.071 (ISS I), <0.0001 (ISS II), and 0.038 (ISS III). The tables below each plot indicate the number of patients at risk over time in each cluster and stage.

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