رسالة جامعية
Functional Screens Identify Vulnerabilities in Acute Leukemia
| العنوان: | Functional Screens Identify Vulnerabilities in Acute Leukemia |
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| المؤلفون: | Ramakrishnan, Ramprasad |
| المصدر: | Lund University, Faculty of Medicine Doctoral Dissertation Series; (2020:91) (2020) ; ISSN: 1652-8220 |
| بيانات النشر: | Lund University, Faculty of Medicine |
| سنة النشر: | 2020 |
| المجموعة: | Lund University Publications (LUP) |
| مصطلحات موضوعية: | Biomedical Laboratory Science/Technology, Acute leukemia, CRISPR, CXCR4, CXCL12, TNFSF13, DUX4, Interleukin 4, leukemia stem cell, macrophage |
| الوصف: | Acute leukemia refers to a group of aggressive hematological malignancies of myeloid and lymphoid lineages termed acute myeloid leukemia (AML) and acute lymphoid leukemia (ALL) respectively. Acute leukemia is characterized by the presence of underlying genetic aberrations which alter the biology of normal hematopoietic cells resulting in the accumulation of immature abnormally differentiated blast cells. In this thesis, we have used advanced molecular techniques to identify vulnerabilities in acute leukemia.In paper I, we performed an in vivo CRISPR-Cas9 screen targeting cell surface genes in murine AML stem cells and showed that CXCR4 is a top cell surface regulator of AML cell growth and survival. Notably, loss of CXCR4 signaling in leukemia cells leads to oxidative stress and differentiation in vivo. In contrast, the CXCR4 ligand CXCL12 is dispensable for leukemia development in recipient mice.To identify key regulators of AML, in paper II, we performed an ex vivo cytokine screen on arrayed molecularly barcoded murine AML cells with a competitive in vivo read-out of their leukemia-initiating capacity. We identified TNFSF13 as a positive regulator of leukemia-initiating cells. We confirmed that TNFSF13 supports leukemia initiation under physiological conditions using Tnfsf13-/- mice. We further showed that TNFSF13 suppresses apoptosis and promotes AML cell proliferation in an NF-κB dependent manner.DUX4-rearranged BCP-ALL is a recently identified molecular subtype characterized by the expression of the IGH- DUX4 fusion gene. With the aim of identifying biological dependencies of this subtype, in paper III, we performed a genome-wide CRISPR-Cas9 screen in the NALM6 cell line, driven by the IGH-DUX4 fusion gene, and two control cell lines. We showed that FNIP1, IRF4 and SYNCRIP are selectively important for the growth and survival of NALM6 cells and that their expression is under the control of the IGH-DUX4 fusion gene. While the deletion of FNIP1 led to the enrichment of transcriptional signatures associated ... |
| نوع الوثيقة: | doctoral or postdoctoral thesis |
| وصف الملف: | application/pdf |
| اللغة: | English |
| ردمك: | 978-91-7619-953-4 91-7619-953-3 |
| العلاقة: | https://lup.lub.lu.se/record/ab96f932-20a5-43e3-abd2-8f1ef881880aTest; urn:isbn:978-91-7619-953-4; https://portal.research.lu.se/files/83128290/Ramprasad_Ramakrishnan_Doctoral_Thesis.pdfTest |
| الإتاحة: | https://lup.lub.lu.se/record/ab96f932-20a5-43e3-abd2-8f1ef881880aTest https://portal.research.lu.se/files/83128290/Ramprasad_Ramakrishnan_Doctoral_Thesis.pdfTest |
| حقوق: | info:eu-repo/semantics/openAccess |
| رقم الانضمام: | edsbas.D28178AE |
| قاعدة البيانات: | BASE |
| ردمك: | 9789176199534 9176199533 |
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