Allogeneic hematopoietic cell transplantation (HCT) is used for patients with high-risk leukemias and bone marrow failure. In HCT, complete donor hematopoiesis is essential for sustained engraftment and prevention of relapse. In the post-transplant setting, clonal preleukemic precursors can re-emerge. In human AML, clonal preleukemic progression occurs in the hematopoietic stem cell [HSC] stage, and each heritable change increases the competitive competence of the clone vs normal HSC. We tested for mammalian germline stem cell competitions, for HSC competitions in aging, and in the progression of competitive HSC in human leukemias based on our early studies of stem cell competitions for germline and soma niches in the colonial chordate Botryllus schlosseri. B. schlosseri is an urochordate model organism that exhibits natural stem-cell mediated chimerism, and shares stem-cell associated gene sets and pathways with human and mouse. When two genetically distinct colonies meet, they either anastomose extracorporeal blood vessels to form a chimera with a common vasculature, or reject one another. In some chimeras, one of the chimeric partners undergoes partial or complete reabsorption. Circulating germ and/or somatic stem cells of one partner in a chimera can compete with and replace the germ line and/or soma of the other partner. Stem cell engraftment in B. schlosseri is regulated on four different levels: 1). fusion or rejection; 2). if fusion occurs, the body of the losing partner is resorbed; 3). competition between circulating somatic stem cells to seed buds for asexual whole body development; and 4). stem cell competition among germ line stem cells, which determines the genotype of the next generation. We discovered the gene (BHF) that controls fusion/rejection, and found that the other levels are also heritable. Thus, genetically distinct strains have somatic stem cells that, in a chimera, vary in their vulnerability to be resorbed, undergo competitions to win or lose differentiated tissue [akin to regeneration], and to win or lose germline niches. Each level of stem cell competition has biological and medical implications: resorption is a model for stem cell loss (failure to bud); somatic competitions relat to stem cell transplant engraftability, and germline stem cell competition determines which genotypes are inherited (fertility). To discover genes and key pathways that regulate stem cell functionality and engraftment potential, we established genetically distinct B. schlosseri strains with different levels of engraftment potential (the ability to not be resorbed in a chimera and/or o win in stem cell competition), sequenced their tissue specific RNAs, and analyzed their gene expression profiles. We arrived at a list of candidate genes and pathways that most likely alter stem cell competitive potential. We will use gene knockdown technology to assess the function of different genes in migrating stem cells in vivo that participate in organogenesis and gonad development. Eventually we will test whether these pathways regulate HSC competitions in allogeneic transplants.
In bone marrow transplantation and similar therapies for leukemias and blood diseases, a major challenge is getting blood-forming stem cells from a donor to survive in a recipient. In this proposed work, we plan to study the mechanisms involved when stem cells from different individuals are combined (as in transplantation) and compete with one another. By identifying and enhancing traits that improve survival of donor cells in the recipient, this research is designed to improve transplant medicine.
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