Abstract
Leukemogenesis was long believed to be solely driven by genetic perturbations in hematopoietic cells but introduction of genetic mutations in the microenvironment demonstrated the ability of niche cells to drive disease progression. The mechanisms by which the stem cell niche promotes leukemia remain poorly understood. Here, using CRISPR-CAS9-mediated cellular barcoding, we demonstrate that leukemia induces niche clonal expansion and we identify the leukemia-secreted pro-angiogenic peptide apelin as the mediator of sinusoidal endothelial cell clonal selection. By genetic overexpression and knock-out, we demonstrate that apelin is necessary and sufficient to promote leukemogenesis via niche clonal and transcriptional remodeling. Our work provides a potential therapeutic opportunity for anti-apelin therapy to treat the leukemic niche at a clonal level.
Authors: Leonard I. Zon1,2*, Olivia Mitchell1,2, Serine Avagyan3, Romain Menard4, Song Yang1,2, Anne L. Robertson1,2, Rajiv Potluri1,2, Jay Shendure5, Romain Madelaine4, Aaron McKenna6, Chloé S. Baron1,2.
Affiliations
1Stem Cell Program and Division of Hematology/Oncology, Boston Children’s Hospital and Dana Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Medical School; Boston MA, USA
2Harvard Stem Cell Institute, Stem Cell and Regenerative Biology Department, Harvard University; Cambridge, MA
3Department of Pediatrics and The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA, USA
4The MDI Biological Laboratory, Bar Harbor, Maine, United States of America
5Department of Genome Sciences and Institute for Stem Cell & Regenerative Medicine, University of Washington; Brotman Baty Institute for Precision Medicine; Seattle Hub for Synthetic Biology; Howard Hughes Medical Institute; Allen Discovery Center for Cell Lineage Tracing, Seattle, WA, USA.
6Dartmouth Cancer Center; Department of Molecular and Systems Biology, Dartmouth College, Hanover, NH
*Corresponding author. Email: zon@enders.tch.harvard.edu