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Nucleoporin Nup358 drives the differentiation of myeloid-biased multipotent progenitors by modulating HDAC3 nuclear translocation

ABSTRACT: We report that Nup358, a nucleoporin linked to acute myeloid leukemia and myeloproliferative neoplasms, is required for the developmental progression of early myeloid progenitors. We found that loss of Nup358 in mice is associated with the accumulation of myeloid-primed multipotent progenitors (MPPs) in bone marrow and the loss of myeloid-committed progenitors and mature myeloid cells. Accumulated MPPs in Nup358 knockout mice are greatly restricted to megakaryocyte/erythrocyte biased MPP2 cells and fail to progress into committed myeloid progenitors.

ORGANISM(S): Mus musculus

PROVIDER: GSE208436 | GEO | 2024/04/11

REPOSITORIES: GEO

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Nucleoporin Nup358 drives the differentiation of myeloid-biased multipotent progenitors by modulating HDAC3 nuclear translocation

Project description:Nucleoporin Nup358 drives the differentiation of myeloid-biased multipotent progenitors by modulating HDAC3 nuclear translocation

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Nucleoporin Nup358 drives the differentiation of myeloid-biased multipotent progenitors by modulating HDAC3 nuclear translocation.

Project description:Nucleoporins, the components of nuclear pore complexes (NPCs), can play cell type- and tissue-specific functions. Yet, the physiological roles and mechanisms of action for most NPC components have not yet been established. We report that Nup358, a nucleoporin linked to several myeloid disorders, is required for the developmental progression of early myeloid progenitors. We found that Nup358 ablation in mice results in the loss of myeloid-committed progenitors and mature myeloid cells and the accumulation of myeloid-primed multipotent progenitors (MPPs) in bone marrow. Accumulated MPPs in Nup358 knockout mice are greatly restricted to megakaryocyte/erythrocyte-biased MPP2, which fail to progress into committed myeloid progenitors. Mechanistically, we found that Nup358 is required for histone deacetylase 3 (HDAC3) nuclear import and function in MPP2 cells and established that this nucleoporin regulates HDAC3 nuclear translocation in a SUMOylation-independent manner. Our study identifies a critical function for Nup358 in myeloid-primed MPP2 differentiation and uncovers an unexpected role for NPCs in the early steps of myelopoiesis.

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Project description:Allogenic hematopoietic stem cell (HSC) transplantation is widely used for treatment of blood disorders to re-establish long-term multi-lineage hematopoiesis. Enhance self-renewal potential of progenitor population to support hematopoiesis offer an alternative and complementary approach to achieve similar or enhance therapeutic effects. Nup98-Hoxa10hd fusion gene (NA) has been shown to confer expansion, anti-stress response and engraftment competitiveness on HSC. However, whether the ectopic expression of NA in multipotent progenitors (MPPs) could enhance their self-renewal potential and confer long-term multi-lineage hematopoiesis remains unknown. In this study, we showed that ectopic expression in MPPs confer long-term multi-lineage hematopoiesis in recipient mice. We further showed that NA upregulated pathways of cell cycle regulation, epigenetic regulation and response to stress in MPPs. These molecular traits increased the self-renewal potential of NA MPPs, which resulting in production of lineage-maintaining committed progenitor cells. Transcriptome analysis of NA myeloid progenitors identified genes regulating hematopoiesis, homeostasis, phosphorylation. In summary, we show that ectopic expression of Nup98-Hoxa10hd fusion gene enhance self-renewal potential of MPPs thus confer long-term multi-lineage repopulating capacity on MPPs, offering promising means to involve MPPs to augment cell source in clinical transplantation settings.

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