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ONTOGENY SHAPES THE ABILITY OF ETV6-RUNX1 TO ENHANCE HEMATOPOIETIC STEM CELL SELF-RENEWAL AND DISRUPT EARLY LYMPHOPOIESIS [in vivo]

ABSTRACT: The ETV6-RUNX1 (E/R) translocation, found in approximately 30% of pediatric B-cell acute lymphoblastic leukemia (ALL) cases, originates prenatally. Although hematopoietic stem cells (HSCs) have been proposed as the cell of origin for E/R-ALL, definitive evidence for this has been lacking. Here, we develop an E/R-inducible transgenic mouse model and observe that E/R rapidly expands the pool of phenotypic HSCs and block early B cell development. By leveraging the reversibility of the model, we demonstrate functional rather than merely phenotypic HSC expansion. At a molecular level, E/R activates immune checkpoint pathways, which is more pronounced in fetal cells. Comparison of fetal and adult HSCs reveals that although E/R disrupts HSC differentiation in both, fetal cells have a competitive advantage, especially in a setting of viral mimicry. These findings provide new insights into the nature of preleukemic clones associated with E/R and suggest potential benefits of immune checkpoint inhibition for their eradication.

ORGANISM(S): Mus musculus

PROVIDER: GSE239340 | GEO | 2024/01/08

REPOSITORIES: GEO

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Project description:Hematopoietic stem cells (HSCs) are at the basis of the hematopoietic hierarchy. Their ability to self-renew and differentiate is strictly controlled by molecular signals produced by their surrounding micorenvironments composed of stromal cells. HSCs first emerge in the AGM (Aorta Gonads Mesonephros) region, amplify in the fetal liver (FL) and are maintained in the adult bone marrow (BM). To further characterize the molecular program of the HSC niches, we have compared the global transcriptome of HSC-supportive and non-supportive stromal clones established from the AGM, FL and BM. Hematopoietic stem cells (HSCs) are at the basis of the hematopoietic hierarchy. Their ability to self-renew and differentiate is strictly controlled by molecular signals produced by their surrounding micorenvironments composed of stromal cells. HSCs first emerge in the AGM (Aorta Gonads Mesonephros) region, amplify in the fetal liver (FL) and are maintained in the adult bone marrow (BM). To further characterize the molecular program of the HSC niches, we have compared the global transcriptome of HSC-supportive line from Fetal Calvaria (OP9) and non-supportive stromal clones from fetal liver (BFC). Hematopoietic stem cells (HSCs) are at the basis of the hematopoietic hierarchy. Their ability to self-renew and differentiate is strictly controlled by molecular signals produced by their surrounding micorenvironments composed of stromal cells. HSCs first emerge in the AGM (Aorta Gonads Mesonephros) region, amplify in the fetal liver (FL) and are maintained in the adult bone marrow (BM). To further characterize the molecular program of the HSC niches, we have compared the global transcriptome of HSC-supportive and non-supportive stromal clones established from fetal liver. We took advantage of stromal clones established from the AGM, FL and BM and tested for their ability to support or not HSCs ex vivo. RNA were extracted from confluent stromal cultures or sorted cells and used for hybridization of Affymetrix (mouse gene 1.0 ST) microarrays.

Dataset Information

ONTOGENY SHAPES THE ABILITY OF ETV6-RUNX1 TO ENHANCE HEMATOPOIETIC STEM CELL SELF-RENEWAL AND DISRUPT EARLY LYMPHOPOIESIS [in vivo]

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