Graduation Year

2009

Document Type

Dissertation

Degree

Ph.D.

Degree Granting Department

Cancer Biology

Major Professor

William G. Kerr, Ph.D.

Committee Member

Alan F. List, M.D.

Committee Member

Gary W. Reuther, Ph.D.

Committee Member

Paul R. Sanberg, Ph.D.

Keywords

SHIP, PI3K, Niche, Extramedullary hematopoiesis, Kinome

Abstract

Blood cells are continuously produced throughout our lifetime by a rare pluripotent cell that primarily resides in the adult bone marrow. This hematopoietic stem cell (HSC) must maintain a careful balance between self-renewal, differentiation and apoptosis in order to support hematopoiesis for such a long duration. Understanding the mechanism of balance between these fates is crucial to our understanding and clinical application of these cells.

From previous studies, we know Src homology 2 domain containing 5' inositol phosphatase 1 (SHIP) plays an important role in HSC homeostasis and function. Most interestingly SHIP impacts HSC homing to the bone marrow niche. An ideal location and environment is essential for HSC to fulfill their physiological roles. Here we present evidence that SHIP is expressed by cells of the HSC niche. Furthermore, SHIP deficiency severely alters this environment and thus damages HSC function.

In addition to the extrinsic effects of a SHIP-deficient microenvironment on HSC, there is an intrinsic requirement for SHIP expression in confining HSC to the bone marrow niche. We previously demonstrated that lack of SHIP leads to an increase in peripheral HSC. Here we demonstrate that SHIP-deficient HSC from the spleen can provide radioprotection and sustained multi-lineage repopulation in lethally irradiated hosts. This indicates extramedullary HSC can function outside the traditional bone marrow niche in SHIP-deficient mice.

Combined, these studies indicate both extrinsic and intrinsic factors contribute to HSC homeostasis and function. In order to better understand the signaling pathways involved in self-renewal and differentiation, we applied an array-based technology to hematopoietic cells at various levels of differentiation. Comparing the phosphorylation signature, or 'kinome', of these cell types can help pinpoint signaling mechanisms important for HSC self-renewal and lineage commitment.

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