Accession Number : AD1048431


Title :   Dysregulated microRNA activity in Shwachman-Diamond Syndrome


Descriptive Note : Technical Report,15 Aug 2016,14 Aug 2017


Corporate Author : Dana-Farber Cancer Institute Boston United States


Personal Author(s) : Novina, Carl


Full Text : https://apps.dtic.mil/dtic/tr/fulltext/u2/1048431.pdf


Report Date : 01 Sep 2017


Pagination or Media Count : 12


Abstract : 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.


Descriptors :   rna sequence analysis , bone marrow , growth factors , ribonucleic acids , stem cells , hematopoiesis , genes , inhibitiors , leukemia


Subject Categories : Biochemistry
      Medicine and Medical Research
      Genetic Engineering and Molecular Biology


Distribution Statement : APPROVED FOR PUBLIC RELEASE