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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 over 50 years ago, the 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 SDS patients. 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 (TGFβ) were dysregulated in SDS hematopoietic stem cells and multipotent progenitors, but not in lineage-committed progenitors. TGFβ inhibitors (AVID200 and SD208) increased hematopoietic colony formation of SDS patient BM. Finally, TGFβ3 and other TGFβ pathway members were elevated in SDS patient blood plasma. These data establish the TGFβ pathway as a novel candidate biomarker and therapeutic target in SDS and translate insights from single cell biology into a potential therapy.

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