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Myelodysplastic neoplasm-associated U2AF1 mutations induce host defense defects by compromising neutrophil chemotaxis
Natalia J Gurule1,2,3, Kenneth C Malcolm4, Chelsea Harris1,2
1Department of Immunology and Genomic Medicine, National Jewish Health, Denver, CO, USA.
Abstract:
Myelodysplastic neoplasm (MDS) is a hematopoietic stem cell disorder that may evolve into acute myeloid leukemia. Fatal infection is among the most common cause of death in MDS patients, likely due to myeloid cell cytopenia and dysfunction in these patients. Mutations in genes that encode components of the spliceosome represent the most common class of somatically acquired mutations in MDS patients. To determine the molecular underpinnings of the host defense defects in MDS patients, we investigated the MDS-associated spliceosome mutation U2AF1-S34F using a transgenic mouse model that expresses this mutant gene. We found that U2AF1-S34F causes a profound host defense defect in these mice, likely by inducing a significant neutrophil chemotaxis defect. Studies in human neutrophils suggest that this effect of U2AF1-S34F likely extends to MDS patients as well. RNA-seq analysis suggests that the expression of multiple genes that mediate cell migration are affected by this spliceosome mutation and therefore are likely drivers of this neutrophil dysfunction.
Insights
Myelodysplastic neoplasm (MDS) patients exhibit impaired host defense due to spliceosome mutations like U2AF1-S34F. This mutation causes neutrophil dysfunction, increasing infection risk in MDS.
Area of Science:
- Hematology
- Immunology
- Molecular Biology
Background:
- Myelodysplastic neoplasm (MDS) is a stem cell disorder often leading to acute myeloid leukemia.
- Infections are a primary cause of mortality in MDS patients, linked to myeloid cell issues.
- Spliceosome gene mutations are common in MDS.
Purpose of the Study:
- To investigate the molecular basis of host defense defects in MDS.
- To examine the impact of the U2AF1-S34F spliceosome mutation on host defense.
Main Methods:
- Utilized a transgenic mouse model expressing the U2AF1-S34F mutation.
- Assessed host defense capabilities and neutrophil chemotaxis in mutant mice.
- Conducted RNA-sequencing (RNA-seq) analysis on neutrophils.
Main Results:
- The U2AF1-S34F mutation induced significant host defense defects in mice.
- A profound neutrophil chemotaxis defect was observed in U2AF1-S34F mice.
- RNA-seq revealed altered expression of cell migration genes, suggesting a mechanism for neutrophil dysfunction.
Conclusions:
- The U2AF1-S34F spliceosome mutation contributes to host defense impairment in MDS.
- Neutrophil chemotaxis defects are a key consequence of this mutation.
- Altered gene expression in cell migration pathways likely drives MDS-related neutrophil dysfunction.
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