Project description:Accumulation of fatty bone marrow (FBM) is one of the key age related changes possibly influencing the blood system. While a link between obesity and cancer evolution has been reported it remains unknown whether FBM can modify the evolution of the early stages of leukemia and clonal hematopoiesis (CH). To address this question, we established different FBM mouse models in immunodeficient mice in whom we can study both mouse and human cells. We focused our studies on two FBM models: 1) after sublethal irradiation; 2) after castration; and in both we used an adipogenesis inhibitor as a control (PPARγ inhibitor). We transplanted both human and mice hematopoietic stem cells (HSCs) carrying DNMT3A mutations into immunodeficient mice with FBM. A significant increase in self-renewal was found when DNMT3AMut-HSCs were exposed to FBM. To better understand the mechanisms of the FBM-CH interaction, we performed single cell RNA-sequencing on HSPCs after FBM exposure in vivo. A 6-10 fold increase in DNMT3AMut-HSCs was observed under FBM conditions in comparison to normal bone marrow. Mutated HSCs from mice exposed to FBM exhibited an activated inflammatory signaling (IL-6 and IFNγ). Cytokine analysis of BM fluid and BM derived adipocytes grown in vitro demonstrated increased IL-6 levels under FBM conditions. Anti-IL-6 neutralizing antibodies significantly reduced the selective advantage of mice derived DNMT3AMut-HSCs exposed to FBM. Overall, paracrine FBM inflammatory signals promote DNMT3A-driven clonal hematopoiesis, which can be inhibited by blocking the IL-6 receptor.

2023-02-19 | E-MTAB-12614 | biostudies-arrayexpress

Inflammatory signals from fatty bone marrow support DNMT3a-driven clonal hematopoiesis (Dnmt3A KI heterozygote subset)

2023-02-19 | E-MTAB-12613 | biostudies-arrayexpress

Aberrant Clonal Hematopoiesis following Lentiviral Vector Transduction of HSPCs in a Rhesus Macaque

Project description:Lentiviral vectors (LVs) are used for delivery of genes into hematopoietic stem and progenitor cells (HSPCs) in clinical trials worldwide. LVs, in contrast to retroviral vectors, are not associated with insertion site-associated malignant clonal expansions and, thus, are considered safer. Here, however, we present a case of markedly abnormal dysplastic clonal hematopoiesis affecting the erythroid, myeloid, and megakaryocytic lineages in a rhesus macaque transplanted with HSPCs that were transduced with a LV containing a strong retroviral murine stem cell virus (MSCV) constitutive promoter-enhancer in the LTR. Nine insertions were mapped in the abnormal clone, resulting in overexpression and aberrant splicing of several genes of interest, including the cytokine stem cell factor and the transcription factor PLAG1. This case represents the first clear link between lentiviral insertion-induced clonal expansion and a clinically abnormal transformed phenotype following transduction of normal primate or human HSPCs, which is concerning, and suggests that strong constitutive promoters should not be included in LVs.

2020-06-25 | GSE153130 | GEO

Aberrant Clonal Hematopoiesis following Lentiviral Vector Transduction of HSPCs in a Rhesus Macaque

Project description:Aberrant Clonal Hematopoiesis following Lentiviral Vector Transduction of HSPCs in a Rhesus Macaque

| PRJNA641566 | ENA

Inflammatory signals from fatty bone marrow support DNMT3a-driven clonal hematopoiesis (NOD/SCID/IL-2Rgc-null subset)

2023-02-19 | E-MTAB-12620 | biostudies-arrayexpress

SRCAP Mutations Drive Clonal Hematopoiesis Through Epigenetic and DNA Repair Dysregulation [ATAC-Seq]

Project description:SRCAP Mutations Drive Clonal Hematopoiesis Through Epigenetic and DNA Repair Dysregulation [ATAC-Seq]

| PRJNA956472 | ENA

PU.1-dependent enhancer inhibition separates clonal hematopoiesis from malignant transformation (ATAC-Seq)

Project description:PU.1-dependent enhancer inhibition separates clonal hematopoiesis from malignant transformation (ATAC-Seq)

| PRJNA789545 | ENA