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This dissertation, Distinctive Functions of the Polycomb Group Protein BMI-1 in Hematopoiesis and Leukemogenesis by Yuk-man, Lam, 林旭文, was obtained from The University of Hong Kong (Pokfulam, Hong Kong) and is being sold pursuant to Creative Commons: Attribution 3.0 Hong Kong License. The content of this dissertation has not been altered in any way. We have altered the formatting in order to facilitate the ease of printing and reading of the dissertation. All rights not granted by the above license are retained by the author. Abstract: Bmi-1 maintains stem cell population in hematopoietic system for replenishment of progenitors and mature cells. It has been shown that Bmi-1 prevents stem cell exhaustion through suppression of cell cycle regulators 〖p16〗 DEGREESINK4a/ 〖p19〗 DEGREESArf and cell differentiation. However, it remains unclear how Bmi-1 maintains self-renewal of hematopoietic stem cells (HSC). To dissect the underlying mechanisms of Bmi-1 in sustaining HSC self-renewal capacity, transcriptome analysis of Bmi-1 knockdown or over-expressing hematopoietic stem and progenitor cells (HSPC) was performed. RNA-Sequencing analysis demonstrated that Bmi-1 de-regulated genes in canonical Wnt signaling, stem-cell quiescence and Tnf/Gzmb-mediated apoptotic signaling in HSPC. Moreover, it was found that Bmi-1 over-expression mildly activated canonical Wnt signaling and de-regulated a panel of Wnt-associated genes Cdkn1a, n-Myc, Fn-1 and Hoxb4 in HSPC. ChIP analysis validated that Bmi-1 binds to the promoter region of Wnt negative regulator Amer2. It suggests that Bmi-1 activates canonical Wnt signaling through suppression of Amer2 in HSPC. More importantly, ChIP analysis validated that Bmi-1 binds to its own promoter region, suggesting that endogenous Bmi-1 expression is maintained through self-regulatory negative feedback mechanism to prevent excessive Wnt signaling activation in HSPC. In view of this, a model of Bmi-1-mediated suppression of Amer2-dependent β-catenin degradation in HSC is proposed. On the other hand, BMI-1-mediated 〖p16〗 DEGREESINK4A leukemogenic pathway has been proposed in human leukemias. However, clinical studies revealed that high BMI-1 expression may not be well-correlated with low 〖p16〗 DEGREESINK4A expression. Importantly, leukemogenic factors such as MLL fusion proteins can regulate 〖p16〗 DEGREESINK4A expression such that the regulation of 〖p16〗 DEGREESINK4A is not dependent on BMI-1. It is therefore unclear how BMI-1 is involved in the process of leukemogenesis. Although it has been demonstrated that high BMI-1 expression was correlated with disease development in human leukemias, recent studies revealed a tumor suppressive role of BMI-1 in cancers, questioning the role of BMI-1 in leukemogenesis. In order to find out the regulatory mechanism of BMI-1 in leukemogenesis, BMI-1 was overexpressed in a panel of leukemia cell lines, including HL-60, MonoMac-6, MV4-11, SEM and Nalm-6. My results demonstrated that BMI-1 over-expression suppresses JAK-STAT signaling through up-regulation of SOCS genes. Moreover, it was found that BMI-1 over-expression suppresses IL7 signaling pathway in SEM leukemia cells, leading to reduced expression of cell survival genes, including PAX5, MCL-1, BCL-2 and BCL-XL. These findings suggest that BMI-1 has a tumor suppressive function in leukemogenesis.In summary, the discoveries of Bmi-1-mediated canonical Wnt signaling and the suppressive role of BMI-1 in JAK-STAT leukemogenic signaling would provide new insights on the understanding of stem cell and leukemia biology, building a foundation for improvement of clinical applications. DOI: 10.5353/th_b5387952 Subjects: LeukemiaHematopoiesisChromo

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