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Functional Rescue of Definitive Hematopoietic Potential in Stem Cells Harboring Telomerase Mutations Associated with Bone Marrow Failure

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Washington University St. Louis United States

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The experiments performed for our DOD BMFRP grant are in line with the original proposal and have significantly increased our knowledge on telomere dysfunction induced BMF. Likewise, we have significantly improved our ability to generate in vitro hematopoietic lineages that can be targeted for future replacement therapies for BMF patients. In brief Aim 1 We have successfully demonstrated that we can significantly increase blood output in DC settings by altering the endogenous processing of TERC in these cells. Silencing of PAPD5 during the hematopoietic differentiation of DKC1 mutant cells increased TERC levels, altered TERC 3 processing, increased telomerase activity, elongated telomeres and improved definitive hematopoietic specification. Aim 2 We have utilized state-of-the-art single cell RNA sequencing technologies to significantly improve our ability to obtain, from human pluripotent stem cells, an entirely new population of definitive hematopoietic progenitors which recapitulate the signal requirements for hematopoietic stem cell specification during embryogenesis. Our analysis identified unappreciated signal pathways relevant to the specification of CDX4 hemogenic mesoderm, such as IL2STAT5, TNF, PI3K, ERK, and NOTCH signaling.

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Technical Report,15 Apr 2017,14 Apr 2019



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Approved For Public Release;

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