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TGF-β signaling underlies hematopoietic dysfunction and bone marrow failure in Shwachman-Diamond syndrome
Cailin E. Joyce, … , Akiko Shimamura, Carl D. Novina
Cailin E. Joyce, … , Akiko Shimamura, Carl D. Novina
Published June 18, 2019
Citation Information: J Clin Invest. 2019;129(9):3821-3826. https://doi.org/10.1172/JCI125375.
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Concise Communication Hematology

TGF-β signaling underlies hematopoietic dysfunction and bone marrow failure in Shwachman-Diamond syndrome

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Abstract

Shwachman-Diamond syndrome (SDS) is a rare and clinically heterogeneous bone marrow (BM) failure syndrome caused by mutations in the Shwachman-Bodian-Diamond syndrome (SBDS) gene. Although SDS was described more than 50 years ago, its molecular pathogenesis is poorly understood due, in part, to the rarity and heterogeneity of the affected hematopoietic progenitors. To address this, we used single-cell RNA sequencing to profile scant hematopoietic stem and progenitor cells from patients with SDS. We generated a single-cell map of early lineage commitment and found that SDS hematopoiesis was left-shifted with selective loss of granulocyte-monocyte progenitors. Transcriptional targets of transforming growth factor beta (TGF-β) were dysregulated in SDS hematopoietic stem cells and multipotent progenitors, but not in lineage-committed progenitors. TGF-β inhibitors (AVID200 and SD208) increased hematopoietic colony formation of SDS patient BM. Finally, TGF-β3 and other TGF-β pathway members were elevated in SDS patient blood plasma. These data establish the TGF-β pathway as a candidate biomarker and therapeutic target in SDS and translate insights from single-cell biology into a potential therapy.

Authors

Cailin E. Joyce, Assieh Saadatpour, Melisa Ruiz-Gutierrez, Ozge Vargel Bolukbasi, Lan Jiang, Dolly D. Thomas, Sarah Young, Inga Hofmann, Colin A. Sieff, Kasiani C. Myers, Jennifer Whangbo, Towia A. Libermann, Chad Nusbaum, Guo-Cheng Yuan, Akiko Shimamura, Carl D. Novina

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Figure 3

TGF-β signaling is selectively activated in SDS stem and multipotent progenitors.

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TGF-β signaling is selectively activated in SDS stem and multipotent pro...
(A) Differentially expressed genes were identified among all SDS versus normal cells and within each cluster: HSC/MPP, CMP, MLP/CLP, or MEP. To aid biological interpretation, this gene set was filtered to focus on genes with FDR-adjusted P value less than .05 and log2 (fold change) greater than 1 in at least one cluster. Plotted are the number of genes that were either up- or downregulated in 1, 2, 3, or 4 clusters. The GMP cluster was excluded due to the paucity of SDS GMPs. Inset pie chart shows the proportion of differentially expressed genes in each cluster. (B) Venn diagram of differentially expressed genes in each cluster that were annotated to the inflammatory response function in Ingenuity Pathway Analysis. The shaded region shows the area of maximal enrichment of TGF-β targets (P = 4.03 × 10–15). (C) Left: split violin for the summed expression of 25 upregulated TGF-β targets and 52 downregulated TGF-β targets in SDS HSCs/MPPs. Right: log2 fold changes (primary axis, bars) and P values (secondary axis, lines) for the gene sets plotted in B. Significance was determined by 2-way ANOVA, with Holm-Sidak’s multiple comparisons test.
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