Molecular pathogenesis of ribosomopathies
Shwachman Diamond Syndrome (SDS) and Diamond Blackfan Anemia (DBA) are two examples of ribosomopathies – diseases characterized by defects in ribosome biogenesis and function. For reasons that are still poorly understood, patients present with congenital anomalies, bone marrow failure in multiple lineages, and an increased predilection to cancers.
Non-coding RNAs including microRNAs and lncRNAs have been shown to regulate body patterning genes, hematopoietic differentiation and development genes, and tumor suppressor and oncogenes. we hypothesized that dysregulated microRNA and lncRNA function can explain why patients with defects in ribosome function present with this constellation of clinical features.
Although SDS and DBA were characterized more than 40 years ago, their molecular pathogenesis has remained obscure in part due to the rarity and heterogeneity of the affected bone marrow progenitors. We performed single cell RNA-sequencing on primary CD34+ hematopoietic progenitors from normal and SDS bone marrows and identified dysregulation of TGF-beta target genes in SDS hematopoietic stem cells and multipotent progenitors, but not in lineage committed progenitors. We have identified lncRNAs expressed in SDS progenitors that might explain why SDS patients present with neutropenia, why SDS patients sometimes progress to pan-anemias, and why approximately 30% of SDS patients progress to an aggressive form of acute myeloid leukemia.
Working with Colin Sieff, we generated a mouse model of DBA to test non-coding RNA function in the pathogenesis of ribosomopathies. Working with Don Ingber, we are testing non-coding RNA function using bone marrow on a chip technology.
Projects are available to work on the biology, dysregulation and modeling of non-coding RNA function in bone marrow failure syndromes.
Non-coding RNAs including microRNAs and lncRNAs have been shown to regulate body patterning genes, hematopoietic differentiation and development genes, and tumor suppressor and oncogenes. we hypothesized that dysregulated microRNA and lncRNA function can explain why patients with defects in ribosome function present with this constellation of clinical features.
Although SDS and DBA were characterized more than 40 years ago, their molecular pathogenesis has remained obscure in part due to the rarity and heterogeneity of the affected bone marrow progenitors. We performed single cell RNA-sequencing on primary CD34+ hematopoietic progenitors from normal and SDS bone marrows and identified dysregulation of TGF-beta target genes in SDS hematopoietic stem cells and multipotent progenitors, but not in lineage committed progenitors. We have identified lncRNAs expressed in SDS progenitors that might explain why SDS patients present with neutropenia, why SDS patients sometimes progress to pan-anemias, and why approximately 30% of SDS patients progress to an aggressive form of acute myeloid leukemia.
Working with Colin Sieff, we generated a mouse model of DBA to test non-coding RNA function in the pathogenesis of ribosomopathies. Working with Don Ingber, we are testing non-coding RNA function using bone marrow on a chip technology.
Projects are available to work on the biology, dysregulation and modeling of non-coding RNA function in bone marrow failure syndromes.