التفاصيل البيبلوغرافية
| العنوان: |
3009 – APELIN-MEDIATED CLONAL EXPANSION OF NICHE ENDOTHELIAL CELLS DRIVES SELECTION OF LEUKEMIC AND NORMAL HSC CLONES. |
| المؤلفون: |
Baron, Chloé1 (AUTHOR), Avagyan, Serine2 (AUTHOR), Mitchell, Olivia3 (AUTHOR), Yang, Song3 (AUTHOR), Mckenna, Aaron4 (AUTHOR), Zon, Leonard3 (AUTHOR) |
| المصدر: |
Experimental Hematology. 2024 Supplement, Vol. 137, pN.PAG-N.PAG. 1p. |
| مصطلحات موضوعية: |
*HEMATOPOIETIC stem cells, *ACUTE myeloid leukemia, *CELL receptors, *EMBRYOLOGY, *STROMAL cells |
| مستخلص: |
Hematopoietic stem and progenitor cells (HSPCs) reside in niches that provide regulatory signals for their function. HSPC clones have been examined by cellular barcoding but the clonality of niche endothelial (ECs) and stromal cells (SCs) is unknown. We hypothesized that leukemia alters niche clones to support leukemogenesis. We developed a zebrafish model of acute erythroid leukemia (AEL) by overexpression of CMYC under the blood specific promotor draculin (drl). We used the GESTALT technique to uniquely barcode single cells using CRISPR-CAS9 during embryonic development. We injected GESTALT embryos with drl:CMYC to induce AEL, barcode HSPCs and their niche. Barcode and scRNA-Seq of ECs revealed a decrease in EC clones (fc=-3.5,p< 0.05) and an AEL-induced angiogenic venous EC population. AEL marrows had less SC clones (fc=-2.1,p< 0.01) and scRNA-Seq of SCs revealed an increased fraction of lepr+ SCs (66 vs 24%). We hypothesized that AEL cells secrete a signal to remodel niche clones. We mined our transcriptome data for ligands upregulated in AEL cells and receptors expressed on ECs and/or SCs. We identified apelin upregulated in AEL cells (p< 0.0001) and receptors aplnra/b specifically expressed on niche ECs. We tested if apelin alone could remodel the niche by overexpressing apelin in HSPCs and found fewer (p=0.004) and larger (p< 0.02) EC clones. HSPC barcode analysis revealed expanded myeloid clones (p< 0.0001) characterized by increased macrophage and erythroid differentiation. Immunohistochemistry on human sections revealed that acute myeloid leukemia (AML) marrows express higher levels APLN and APLNR compared to controls demonstrating the relevance of apelin signaling in human disease. Our data reveals that apelin signaling mediates AEL-induced clonal and transcriptional remodeling of niche ECs to promote disease progression. [ABSTRACT FROM AUTHOR] |
| قاعدة البيانات: |
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