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Delineation of Molecular Mechanisms Underlying the Pathobiology of ALK-positive Anaplastic Large-cell Lymphoma Open Access


Other title
Type of item
Degree grantor
University of Alberta
Author or creator
Supervisor and department
Raymond Lai (Laboratory Medicine and Pathology)
Examining committee member and department
Yangxin Fu (Experimental Oncology)
Robert Ingham (Medical Microbiology and Immunology)
Medical Sciences-Laboratory Medicine and Pathology

Date accepted
Graduation date
2017-06:Spring 2017
Doctor of Philosophy
Degree level
ALK-positive anaplastic large-cell lymphoma (ALK+ALCL) is a rare type non-Hodgkin lymphoma of null/T cell original, preferentially occurs in children and young adults. Approximately 85% of ALK+ALCL patients carry the gene translocation t(2;5)(p23;q35), which results in the generation of the chimeric protein − NPM-ALK, a key oncogenic driver of this disease. NPM-ALK interacts and activates a wide range of molecules, including STAT3, ERK1/2, and PI3K, thus triggering the cell proliferation and anti-apoptotic effects. In this thesis, I further explored the molecular mechanisms of the pathobiology of ALK+ALCL from different perspectives, and hypothesized that the pathobiology of ALK+ALCL, such as tumorigenecity, chemoresistance and cancer stemness, can be attributed to novel NPM-ALKꟷregulated biochemical defects as well as signaling pathways that are not directly linked to NPM-ALK. STAT1 is generally considered as a tumor suppressor and reported to antagonize STAT3 transcriptional activity in some cell models. However, the biological function of STAT1 has not been studied in ALK+ALCL. This study firstly reported that STAT1 expression is decreased in ALK+ALCL cell lines and patient samples; and NPM-ALK is directly responsible for the downregulation of STAT1, as it promotes STAT1 phosphorylation at Y701 and, thereby, downregulates STAT1 in a STAT3-dependent proteasome pathway. Furthermore, results showed that STAT1, if overexpressed to a relatively high level, functions as a potent tumor suppressor in ALK+ALCL by attenuating STAT3 transcriptional activity and inducing the expression of IFNγ which further activates the STAT1 signaling. The Lai lab previously unearthed two distinct cell populations in ALK+ALCL cell lines that are differentially responding to a Sox2 reporter, with cells responsive to the reporter (RR) being more tumorigenic and chemoresistant than cells unresponsive to the reporter (RU). Although Sox2 is implicated in the RU/RR dichotomy, the expression level of Sox2 is not different between RU and RR cells, suggesting the involvement of other factor(s). This study reported that MYC is one of the key factors in the RU/RR dichotomy, as it is highly expressed in RR cells as compared to RU cells. The high level of MYC was firstly reported to promote Sox2 DNA binding and its transcriptional activity in RR cells. More evidence suggested that it is the highly active Wnt/β-catenin pathway in RR cells that confers to the high expression of MYC. The transcriptionally active Sox2 in RR cells in return upregulates the Wnt/β-catenin pathway, which thereafter promotes the expression of MYC, thus forming a positive forward loop. In conclusion, the positive forward loop involving the Wnt/β-catenin/MYC/Sox2 axis defines a highly tumorigenic small cell population in ALK+ALCL. The molecular mechanisms underlining tumor plasticity, especially in hematological malignance, is not fully understood. This study reported that H2O2, a potent oxidative stress inducer, can convert a fraction of RU cells derived from ALK+ALCL cells to RR cells (converted RR cells), supporting the existence of tumor plasticity in hematological malignancy. The converted RR cells have adopted the RR cells’ phenotypes (including chemoresistance to doxorubicin, a widely used chemotherapeutic drug for ALK+ALCL patients, clonogenicity and sphere-forming ability) and biochemical features (the increased expression of Wnt/β-catenin/MYC and Sox2 downstream targets). Similar biological changes were observed in RR cells upon oxidative challenge. Furthermore, more evidence showed that the activated Wnt/β-catenin/MYC/Sox2 axis upon oxidative stress is required for the RU to RR cells conversion since pharmacological inhibition of β-catenin/MYC or siRNA knockdown of Sox2 significantly abrogated the conversion. In conclusion, this study has demonstrated a novel experimental model in which acquisition of tumorigenicity and cancer stem-like features can be induced by oxidative stress in ALK+ALCL, a hematologic malignancy, through the activation of Wnt/β-catenin/MYC/Sox2 axis. Overall, characterization of these molecular mechanisms underlying the tumorigenesis of ALK+ALCL has furthered the understanding of the pathobiology of this disease and also provided potential therapeutic targets for ALK+ALCL patients that are less responsive or resistance to conventional chemotherapy.
This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for the purpose of private, scholarly or scientific research. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.
Citation for previous publication
Wu C, Molavi O, Zhang H, Gupta N, Alshareef A, Bone K, Gopal K, Wu F, Lewis J, Douglas D, Kneteman N, and Lai R. STAT1 is phosphorylated and down-regulated by the oncogenic tyrosine kinase NPM-ALK in ALK-positive anaplastic large-cell lymphoma. Blood. 2015.126:336-345.Wu C, Zhang H, Gupta N, Alshareef A, Wang Q, Huang Y, Lewis JT, Douglas DN, Kneteman NM, and Lai R. A positive feedback involving the Wnt/β-catenin/MYC/Sox2 axis defines a highly tumorigenic cell subpopulation in ALK-positive anaplastic large-cell lymphoma. Journal of Hematology and Oncology, 2016.9(1):120.

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