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Next Generation Sequencing Facilitates Quantitative Analysis of Wild Type and Klf12-/- Lymphocyte Transcriptomes

ABSTRACT: The goal of this study is to determine the role of the transcription factor, Klf12, in mouse NK cells. Transcriptome profiling by RNA-Seq of wild-type and Klf12-deficient mouse CD4+ T cells, CD8+ T cells, B cells, and NK cells. We found that Klf12-deficient mouse NK cells express more transcripts of Btg3 and have a proliferative impairment compared to wild-type mouse NK cells in a competitive setting.

ORGANISM(S): Mus musculus

PROVIDER: GSE128962 | GEO | 2020/04/13

REPOSITORIES: GEO

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Project description:We are studying the natural history, pathogenesis and treatment of patients with WHIM syndrome, an immunodeficiency disorder characterized by warts, hypogammaglobulinemia, recurrent infections and neutropenia usually due to autosomal dominant gain-of-function mutations in chemokine receptor CXCR4. We have identified a patient born with WHIM syndrome and the WHIM mutation CXCR4R334X who has been disease-free for 20 years and who lacks CXCR4R334X in myeloid cells, the cells that drive disease manifestations. She is a genetic and hematopoietic mosaic, since she still has the mutation in lymphoid cells and non-hematopoietic cells. Cytogenetics and microarray analysis revealed that the mechanism of loss of the mutation was deletion of the mutant allele from one copy of chromosome 2. Whole genome sequencing of patient neutrophil and skin fibroblast genomic DNA revealed that the mechanism of deletion was chromothripsis, a process of chromosome shattering resulting in deletions and rearrangements of the non-deleted chromosomal segments. In the patient, this process evidently occurred in a single hematopoietic stem cell (HSC), resulting in deletion of the disease allele CXCR4R334X and one copy of 163 other genes on chromosome 2. This HSC evidently acquired a growth advantage and repopulated the HSC population and the myeloid lineage. Consistent with this, studies using gene targeted mice in competitive bone marrow transplantation experiments revealed that selective Cxcr4 haploinsufficiency (inactivation of one copy of Cxcr4 and not of any other genes) was sufficient to confer a strong engraftment advantage over bone marrow cells from wild type mice as well as bone marrow cells from a mouse model of WHIM syndrome. These results suggest that CXCR4 knockdown may be a useful strategy to enhance bone marrow engraftment in the absence of toxic bone marrow conditioning regimens.

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Next Generation Sequencing Facilitates Quantitative Analysis of Wild Type and Klf12-/- Lymphocyte Transcriptomes

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