All ETDs from UAB

Advisory Committee Chair

Ravi Bhatia

Advisory Committee Members

Lalita Shevde-Samant

Christopher A Klug

Xinyang Zhao

Zhi-Xiang Xu

Document Type

Dissertation

Date of Award

2016

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Treatment of chronic myeloid leukemia (CML) with BCR-ABL tyrosine kinase inhibitors (TKIs) fails to eradicate the leukemia stem cells (LSCs) from which the disease arises. Previously, we and others have shown that LSC persistence is related to kinase-independent mechanisms and mediated in part by signals from the bone marrow microenvironment (BMM). Specifically, we found that WNT signaling from the BMM may contribute to preservation of CML LSC following TKI treatment. Wnt secretion and activity requires their palmitoylation by the Porcupine acyltransferase (PORCN). WNT974 (formerly LGK974) is a potent PORCN inhibitor that blocks WNT signaling and demonstrates in vivo efficacy against Wnt-dependent tumors. In chapter 2, we investigated the role of WNT ligand secretion in the maintenance of CML LSC. WNT974 efficiently antagonized WNT signaling in CML LSC, and in combination with nilotinib (Nil) significantly inhibited the clonogenic potential and decreased engraftment of CML LSC. Treatment with nilotinib + WNT974 also markedly inhibited LSC growth in vivo, inhibited secondary transplant capacity, and enhanced survival of mice after discontinuation of treatment. We further demonstrate that the enhanced sensitivity of CML LSC to Wnt stimulation may be explained, at least in part, by their increased expression of FZD4 receptor. There is increasing interest in the role of the BMM in promoting leukemia stem cell (LSC) maintenance, resistance to conventional chemotherapy and targeted therapies, and ultimately disease relapse. Thus, in chapter 3, we investigated the distribution of BM skeletal stem cell hierarchy in CML and found that the bone-forming (Thy) and stroma-forming (6C3) progenitors are expanded. We also found that these mSSC subsets differentially support HSC and LSC long-term repopulation activity due to altered expression profile of key cytokines and WNT pathway members. Finally, in chapter 4, we discuss the significance of our findings and the potential of understanding the crosstalk between the BMM and LSC, with special focus on the Wnt/β-catenin signaling. We also discuss the potential approaches one can utilize to study this complex bi-directional mechanism. Furthermore, we also discuss how we can exploit these observations to create novel strategies for targeting therapy-resistant LSC to achieve relapse-free survival in leukemic patients.

Share

COinS