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. 2024 Jun;38(6):1427-1431.
doi: 10.1038/s41375-024-02249-z. Epub 2024 Apr 17.

Mutations in the splicing factor SF3B1 are linked to frequent emergence of HLA-DRlow/neg monocytes in lower-risk myelodysplastic neoplasms

Susann Winter #  1 , Marie Schneider #  2 , Uta Oelschlaegel  1 , Giulia Maggioni  3   4 , Elena Riva  3   4 , Marco Gabriele Raddi  5 , Sara Bencini  6 , Benedetta Peruzzi  6 , Desmond Choy  3 , Rita Antunes Dos Reis  3 , Esther Güse  7   8 , Christopher Lischer  7   8 , Julio Vera  7   8 , Jessica A Timms  3 , Nicolas Sompairac  3 , Katja Sockel  1 , Antonella Poloni  9 , Antje Tunger  10   11 , Matteo Giovanni Della Porta  4   12 , Valeria Santini  5 , Marc Schmitz  10   11   13 , Uwe Platzbecker #  2   13   14 , Shahram Kordasti #  15   16   17
Affiliations

Mutations in the splicing factor SF3B1 are linked to frequent emergence of HLA-DRlow/neg monocytes in lower-risk myelodysplastic neoplasms

Susann Winter et al. Leukemia. 2024 Jun.
No abstract available

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Conflict of interest statement

SW, MS, UO, GM, ER, MGR, SB, BP, DC, RADR, EG, CL, JV, JT, NS, KS, AP, AT, MGDP, VS, MS, and UP declare no competing financial interests. SK has received research support and honoraria from Novartis (advisory board, speakers bureau), Alexion (speakers bureau), Beckman Coulter (speakers bureau), MorphoSys (research support), and Pfizer (speakers bureau). None of these are relevant to the current work.

Figures

Fig. 1
Fig. 1. Monocytes with HLA-DRlow/neg immunophenotype emerge frequently in the BM of SF3B1mut MDS.
A T-REX plot of regions of significant change on Uniform Manifold Approximation (UMAP) axes for CD45+ BM-MNCs stained for CyTOF showing distinct LR-MDS-specific (dark red, ≥95% of cells are contributed by LR-MDS samples) and HD-specific (dark blue, ≥95% of cells are contributed by HD) cell clusters. 14 LR-MDS (mean age = 74 years, 4 women, 10 men) and 4 HD (mean age = 58 years, all men) were included in the analysis. LR-MDS group comprises SF3B1K700E (n = 5, orange dots; mean age = 75 years, 2 women, 3 men) and SF3B1wt (n = 9, blue dots; mean age = 74 years, 2 women, 7 men) patients. Top 10 Marker Enrichment Modeling (MEM) labels with enrichment scores are shown for statistically significant LR-MDS-specific clusters (cutoff  >2000 cells) indicated on T-REX plot. B T-REX analysis of CD45+ BM-MNCs stained for CyTOF showing distinct SF3B1K700E-specific (dark red) and SF3B1wt-specific (dark blue) cell clusters. Top 10 MEM labels are shown for statistically significant and trend clusters (cutoff  >1000 cells) indicated on T-REX plot. A, B Labels on T-REX plot indicate major immune cell subsets (myeloid cells, NK cells, γδ T cells, CD4+ and CD8+ T cells, B cells). C T-REX analysis of CD33+ CD14+ pre-gated monocytes showing SF3B1K700E-specific (dark red) and SF3B1wt-specific (dark blue) clusters. Cluster 795 depicts a distinct HLA-DRlow/neg monocyte subset in SF3B1K700E LR-MDS (NOTE: this cluster is not related to cluster 795 shown in (A)). HLA-DR expression was projected onto UMAP axes. A–C Two-sided Mann–Whitney-U-test/Wilcoxon rank-sum test was performed for indicated clusters (p < 0.05 was considered significant; p-values are shown in brackets). Box plots depict median, IQR (lower and upper hinges), and 1.5 times the IQR (lower and upper whiskers extend to values within 1.5 times the IQR from the hinge). (D) Percentage of CD33+ CD14+ BM monocytes with HLA-DRlow/neg immunophenotype in HD (median = 9.7, IQR = 8 [n = 9, mean age = 69 years, 6 women, 3 men]), SF3B1mut (median = 37.9, IQR = 34.9 [n = 17; orange dots, K700E; light orange-filled circles, nonK700E including one K666R, one E622D, one H662Y, and one Y623C; mean age = 71 years, 6 women, 11 men]), and SF3B1wt (median = 6.3, IQR = 11.2 [n = 16, mean age = 66 years, 8 women, 8 men]) MDS assessed by diagnostic FCM of freshly stained BM samples (Kruskal–Wallis test with Dunn’s post-hoc test [Bonferroni adjusted p-values]). E Representative HLA-DR staining on CD33+ CD14+ BM monocytes. The black line indicates the set threshold distinguishing low or negative from high HLA-DR expression. F Percentage of CD33+ CD14+ BM monocytes with HLA-DRlow/neg immunophenotype in four SF3B1K700E MDS patients over time. Patients #4, #10, and #11 harbor an isolated SF3B1K700E mutation.
Fig. 2
Fig. 2. Classical monocytes (CM) from SF3B1K700E LR-MDS exhibit dysregulated immune gene expression and splicing.
A Metascape pathway and process enrichment analysis of up- and downregulated genes in peripheral blood CM from SF3B1K700E LR-MDS (n = 3) compared to HD (n = 3). The top 10 and 20 representative terms are shown for up- and downregulated genes, respectively. B IPA core pathway analysis showing the predicted activity (cutoff z-score of >|0.5|) of overrepresented annotations (p-value < 0.05 [right-tailed Fisher’s exact test]) based on the list of DEG (PostFC ≥ 2 or ≤0.5, PPDE > 0.95) in SF3B1K700E or SF3B1wt compared to HD CM (n = 3 per group). C Alternative splicing (AS) signature in SF3B1K700E CM: Volcano plot highlighting differentially spliced genes (DSG) with inclusion level difference (ILD) > |0.2| and pie chart showing distribution of differential splicing event types detectable in SF3B1K700E LR-MDS compared to HD CM using rMATS. Shown below is the pathway and process enrichment analysis of DSG using Metascape (top 20 enriched terms across input DSG). D Cytokine secretion of LPS-stimulated CM was determined by Luminex analysis. Heatmap depicts Log2-transformed normalized median fluorescence intensity values for the indicated cytokines produced by HD, SF3B1K700E, or SF3B1wt (n = 3 per group) LR-MDS classical monocytes following in vitro LPS stimulation. The variant allele frequency (VAF) of SF3B1K700E mutation in CM is shown on the left side. AS alternative splicing, A3SS alternative 3’ splice site, A5SS alternative 5’ splice site, DEG differentially expressed genes, DSG differentially spliced genes, MXE mutually exclusive exon, RI retained intron, SE skipped exon.
See this image and copyright information in PMC

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