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Dysregulated microRNA activity in Shwachman-Diamond Syndrome

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Technical Report,15 Aug 2016,14 Aug 2017

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Dana-Farber Cancer Institute Boston United States

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Shwachman-Diamond Syndrome SDS is an underdiagnosed and clinically-heterogeneous disorder resulting in bone marrow BM failure. SDS is caused by biallelic mutations in the SBDS gene, which normally functions in ribosomal subunit joining and mitotic spindle stabilization. Despite these insights, the molecular pathways leading to BM failure are unknown because the hematopoietic stem and progenitor cells HSPC affected by SBDS mutations are rare and heterogeneous. To investigate the mechanisms of SDS pathogenesis, we performed single cell RNA-sequencing on primary CD34 HSPC from normal and SDS BM. 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 GMPs. Differential gene expression analysis revealed dysregulation of TGF target genes in SDS hematopoietic stem cells HSCs and multipotent progenitors MPPs, but not in lineage-committed progenitors. Proteomic analysis of primary SDS patient plasma identified increased TGF-family ligand production. Treatment of SDS patient BM with TGF inhibitors increased hematopoietic colony formation, supporting a causative role for TGF-signaling in SDS pathogenesis. These data establish TGF as a therapeutic target in SDS and translate insights from single cell biology into a novel potential therapy.

Subject Categories:

  • Biochemistry
  • Medicine and Medical Research
  • Genetic Engineering and Molecular Biology

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