Abstract:
Background: Acute myeloid leukemia (AML) is one of the most frequent and heterogeneous hematological malignancies in adults. Despite the advances in the understanding and treatment of AML, this leukemia still associates with poor prognosis. Mutations in Nucleophosmin-1 occur in around one third of AML patients (NPM1c AML). EAPB0503 is a potent derivative of Imiquimod, a toll like receptor (TLR) agonist. In NPM1c AML, EAPB0503 induced selective degradation of NPM1c, restored wilt type NPM1 (wt-NPM1) nucleolar localization in vitro, and ex vivo treated patients’ blasts and reduced leukemia burden in NPM1c AML xenograft mice. Methods: We used two AML cell lines, OCI-AML2 and OCI-AML3 expressing wt-NPM1 and NPM1c respectively. In vitro, the effect of EAPB0503 on cell growth, cell cycle, expression levels and localization of NPM1c, TLR7, TLR8, MyD88, SENP6, IκBα and p-IκBα were assessed. Results: EAPB0503 inhibited OCI-AML3 proliferation in a time-dependent manner and led to NPM1c degradation. This was accompanied by restored wt-NPM1 nucleolar localization in NPM1c AML cells and a pre-G0 accumulation. Importantly, EAPB0503 upregulates Toll-like receptors 7 and 8 (TLR7 and TLR8), activates their downstream component MyD88, downregulates SENP6, and induces the phosphorylation and degradation of IκBα, thus probably activating the NF-κB pathway. In vivo, immunocompromised mice were injected intravenously with either cell lines. EAPB0503 was administered by intra-peritoneal injection, every other day, for 3 weeks. EAPB0503 selectively prolonged survival of OCI-AML3 xenograft mice and reduced the number of bone marrow blasts along with NPM1c degradation. Conclusions: These findings expand the anti-leukemic use of EAPB0503 in NPM1c AML and warrant a broader clinical evaluation of this immunomodulatory drug in NPM1c AMLs.
Description:
Thesis. M.Sc. American University of Beirut. Department of Experimental Pathology, Immunology and Microbiology. Faculty of Medicine 2019. W 4 S626t 2019; Advisor: Dr. Hiba El Hajj, PhD, Associate Professor, Department of Experimental Pathology, Microbiology and Immunology ; Co-advisor: Marwan El-Sabban, Professor, Department of Anatomy, Cell Biology and Physiological Sciences ; Committee members: Dr. Ghassan M. Matar, PhD, Professor and Chairperson, Department of Experimental Pathology, Microbiology and Immunology ; Dr. Rami Mahfouz, Professor, Department of Pathology and Laboratory Medicine.
Includes bibliographical references (leaves 73-83)