Hematopoiesis is now recognized as the integrated activity of multiple, largely progenitor clones with heterogeneous behavior. Clonal complexity is thought to diminish with age and human studies suggest that oligoclonal hematopoiesis with disease associated mutations is common. The presence of such clones incurs a substantial risk of hematologic neoplasia and all cause mortality. The overall goal of this proposal is to understand the molecular drivers of clonal behavior under stress conditions and to test whether modifying those drivers is capable of changing the relative competitive balance of normal and abnormal, risk bearing clones in animal models. We will use techniques of fluouresence clonal tracking in the mouse developed by us and compare these with retrotransposon clonal marking techniques in the mouse of Carmago and fluorescence clonal tracking techniques in the zebrafish developed by Zon. Further, we will characterize genetic characteristics of clones at single cell resolution using techniques of Tenen and define ncRNA candidate molecular drivers with Tenen. Finally, we will target epigenetic modifiers defined by Orkin, Tenen and Zon to test the impact on clonal competition between normal and mutant clones in vivo. Combined these complementary and collaborative approaches will point to methods for altering competitive relationships in hematopoiesis in favor of normal cells.

Public Health Relevance

RESEARCH NARRATIVE Blood cell production depends upon populations of primitive cells generating offspring in a regulated manner appropriate to need. It is now clear that the primitive populations of cells are a collection of highly distinctive cells some of which can become rogue creating blood disease. Our goal is to understand how individual primitive cells respond to particular challenges, defining the molecular basis for their behavior. In this way, we plan to create a roadmap for interventions to improve blood cell production under conditions of stress and disease.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
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Heart, Lung, and Blood Initial Review Group (HLBP)
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Yang, Yu-Chung
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Massachusetts General Hospital
United States
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Wattrus, Samuel J; Zon, Leonard I (2018) Stem cell safe harbor: the hematopoietic stem cell niche in zebrafish. Blood Adv 2:3063-3069
Rodriguez-Fraticelli, Alejo E; Wolock, Samuel L; Weinreb, Caleb S et al. (2018) Clonal analysis of lineage fate in native haematopoiesis. Nature 553:212-216
Sridhar, Radhakrishnan; Takei, Hisashi; Syed, Riyaz et al. (2018) Styryl Quinazolinones as Potential Inducers of Myeloid Differentiation via Upregulation of C/EBP?. Molecules 23:
Gonzalez, David; Luyten, Annouck; Bartholdy, Boris et al. (2017) ZNF143 protein is an important regulator of the myeloid transcription factor C/EBP?. J Biol Chem 292:18924-18936