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The role of Toll/interleukin-1 receptor adaptor protein in the pathogenesis of myelodysplastic syndromes

University of British Columbia

Hematopoiesis is a process essential for the maintenance of cells that mediate many vital functions such as the production of red blood cells necessary for transportation of oxygen and the removal of carbon dioxide from the body. It is also required for the production of platelets which are necessary for clotting, and the various types of white blood cells that make up the innate and adaptive immune systems that protect against viral, microbial, and parasitic infections. The cell responsible for the generation of all the downstream effector cells, the hematopoietic stem cell (HSC), is generated during embryogenesis. Through a series of symmetric and asymmetric cell divisions, the HSC is capable of maintaining all the cells of the hematopoietic hierarchy throughout the lifespan of an organism. A variety of genetic and epigenetic cues are necessary to maintain homeostasis, and perturbations in these cues lead to the development of hematopoietic malignancies and myelodysplastic syndromes. In recent years the innate immune pathway has emerged as an important player in hematopoietic homeostasis. This dissertation examines the role of dysregulation of innate immune signaling in the development of the myelodysplastic syndromes, one of the most common hematological malignancies. Using a murine bone marrow transplantation assay, I show that overexpression of the innate immune signaling adaptor, TIRAP, results in perturbations in normal hematopoiesis. Overexpression of TIRAP in the hematopoietic compartment results in an inability to produce mature hematopoietic cells, leading to pancytopenia and bone marrow failure (BMF). TIRAP-induced BMF is a result of both autonomous and non-autonomous effects mediated by the cytokine IFNγ. Interestingly, in an environment depleted of IFNγ, TIRAP-transplanted mice develop a myeloproliferative neoplasm suggesting that TIRAP activates both myelosuppressive pathways (through IFNγ) as well as myeloproliferative pathways. IFNγ acts in a paracrine manner inhibiting osteoclast proliferation and maturation in the bone marrow microenvironment, thus disrupting the HSC niche. In summary, this thesis shows the importance of immune regulation in hematopoietic homeostasis. Furthermore, it shows how defects in the hematopoietic stem/progenitor compartment can translate into a defect in the stem cell niche, contributing further to marrow failure and disease progression.

Text

2016-06-30

Attribution-NonCommercial-NoDerivs 2.5 Canada

http://hdl.handle.net/2429/53969

Interdisciplinary Oncology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/2.5/ca/