Hematopoietic stem cells (HSCs) maintain homeostasis of the blood and immune system throughout life. They are tightly regulated by their microenvironmental niche in the bone marrow. Mounting evidence suggests that chronic myeloid leukemia (CML) arise from mutant HSCs. These diseased leukemia stem cells (LSCs) hijack the HSC mechanisms to sustain the cancer growth and cause relapse. Eradication of LSCs is thus pivotal to cure CML. The discovery of the causing active Bcr/abl kinase mutation in CML and the development of tyrosine kinase inhibitors against Bcr/abl have revolutionized the way we treat CML. Tyrosine inhibitors become the first line of treatment against CML. Although tyrosine kinase inhibitors (e.g. imatinib) can manage the disease, they do not eliminate CML-SCs. A major CML-SC resistant mechanism is the protection offered by the bone marrow niche. Elucidating the niche regulatory mechanisms and target the niche protection mechanisms will help eliminate CML-SCs to better treat CML. However, little is known about the LSC niche. The goal of the proposed research is to characterize how thrombopoietin (TPO), an extrinsic factor, regulates HSCs and LSCs. TPO pathway is required for primitive HSC maintenance in mice and humans. It is not known where Tpo-expressing bone marrow cells create a special niche for primitive HSCs. Furthermore it is not known whether TPO pathway is `hijacked' by CML-SCs for their maintenance. Here, we will identify cellular source of TPO in the bone marrow. Then we will test what cells represent functionally important source for HSC maintenance in vivo. Finally, we will functionally test the role of TPO in CML progression with the focus on CML-SCs in vivo. The results of these studies are expected to not only provide new insights on how the bone marrow niche regulates HSC self-renewal and function, but also have the potential to identify therapeutic targets for CML in the niche.
The experiments in this proposal are aimed at elucidating the roles of thrombopoietin on the regulation of HSCs and LSCs. The information gained through this project will advance our understanding of the extrinsic mechanisms that regulate HSC and LSC maintenance. This may help improve methods of ex vivo expansion of HSCs for clinical use and can aid in developing novel therapeutic methods to target the niche to treat hematological diseases such as CML.
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