TGFß signaling underlies hematopoietic dysfunction and bone marrow failure in Shwachman-Diamond Syndrome.
J Clin Invest
; 129(9): 3821-3826, 2019 06 18.
Article
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| MEDLINE
| ID: mdl-31211692
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 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 (TGFß) were dysregulated in SDS hematopoietic stem cells and multipotent progenitors, but not in lineage-committed progenitors. TGFß inhibitors (AVID200 and SD208) increased hematopoietic colony formation of SDS patient BM. Finally, TGFß3 and other TGFß pathway members were elevated in SDS patient blood plasma. These data establish the TGFß pathway as a novel candidate biomarker and therapeutic target in SDS and translate insights from single cell biology into a potential therapy.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Médula Ósea
/
Células Madre Hematopoyéticas
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Factor de Crecimiento Transformador beta1
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Síndrome de Shwachman-Diamond
Límite:
Adolescent
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Adult
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Child
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Humans
Idioma:
En
Revista:
J Clin Invest
Año:
2019
Tipo del documento:
Article
País de afiliación:
Estados Unidos