Date of Award

2017

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Cell & Molecular Biology

First Advisor

Wei Tong

Abstract

Hematopoietic stem cells (HSCs) are rare cells that reside in bone marrow. HSCs function to give rise to all blood cells through proliferation and differentiation, but also to HSCs in a tightly regulated process known as self-renewal. It is for these abilities that stem cells stand out from progenitors and other short-lived cells and which allows them to last a lifetime. Self-renewal remains mechanistically enigmatic but central to the biology and long lifespan of HSCs. Because HSCs are so long-lived they face numerous genomic insults and therefore mechanisms of genome stability are also central to HSC function throughout life.

This thesis examines the role of an adaptor protein known as LNK (SH2B3), which negatively regulates a central cytokine signaling axis in HSCs, in regulating HSC self-renewal and genome stability. HSCs in Lnk-/- mice are expanded, and endowed with enhanced proliferative and self-renewal capabilities. Given this superiority, this thesis first investigates the impact of LNK deficiency in context of a bone marrow failure syndrome, Fanconi Anemia (FA), where HSCs accumulate fatal levels of genomic insults and cannot function. Superimposed on the deletion of a central gene in FA, FANCD2, Lnk deficiency rescues HSC function through restoring genome stability at sites of stress encountered during DNA duplication.

Second, using a model that is capable of tracking HSC divisions in vivo, this thesis investigates the in vivo self-renewal dynamics of Lnk deficient HSCs. On a population level, HSCs exist along a continuum of states between fully functional HSCs and progenitors, and LNK deficiency tips the balance towards HSCs. This is a cell-intrinsic process, and may be regulated by gene expression-dependent and –independent functions of LNK.

Taken together, the data presented in this thesis describes a novel role for cytokine signaling in HSC genome stability, and deepens our understanding of how LNK influences self-renewal and genome stability. Hopefully, these findings can contribute to the foundation of work that may result in the development of novel therapeutic approaches to treat bone marrow failure and genome instability in HSCs.

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Cell Biology Commons

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