): Background: The identification of FTO as the first N6-methyladenosine RNA demethylase have spurred immense interest in study of the regulatory functions of m6A modifications. Despite the critical impacts of the m6A modifications in various fundamental biological processes, the function (and molecular mechanism) of FTO in cancers, such as acute myeloid leukemia (AML), has yet to be studied. AML is one of the most common and fatal forms of hematopoietic malignancies. Despite the improved risk stratifications and treatment- adapted strategies, >70% of AML patients cannot survive over 5 years due to drug resistance. Thus, it is critical to better understand molecular mechanisms underlying pathogenesis and drug response of AML, which may lead to the development of effective novel therapeutic strategies to treat AML. Our data suggest that FTO likely plays a critical oncogenic role in the pathogenesis of MLL-rearranged AML and in drug response of t(15;17) AML. We show that FTO is highly expressed in AMLs carrying t(11q23)/MLL-rearrangements, t(15;17), NPM1 mutations and/or FLT3-ITD, namely FTO-high AMLs, which are more sensitive to all-trans-retinoic acid (ATRA) and/or arsenic trioxide (ATO) treatment than the other AML subtypes. ATRA/ATO-based differentiation therapy has transformed t(15;17) AML from a highly fatal disease to a highly curable one. However, the role of FTO and the underlying molecular mechanism in the pathogenesis and drug response of FTO-high AMLs are elusive. Objective/Hypothesis: We hypothesize that FTO, as a major m6A eraser, plays a critical role in both pathogenesis and drug response of FTO-high AMLs through epigenetically regulating expression of its targets.
Specific Aims : (1) To determine the role of FTO in both development and maintenance of FTO-high AMLs; (2) To identify critical direct targets of FTO and the regulatory mechanism(s) in FTO-high AMLs; and (3) To determine the role and underlying mechanism of FTO in the response of FTO-high AMLs to ATRA and/or ATO treatment. Study Design: 1) We will use the Fto knockout model coupled with mouse bone marrow transplantation (BMT) leukemia models to investigate the pathological function of FTO in both development and maintenance of various subtypes of FTO-high AMLs and in the self-renewal of relevant leukemia stem/initiating cells (LSCs/LICs). 2) We will identify critical direct target genes of FTO by integrating m6A distribution data with FTO-RNA interaction data, and will decipher the molecular mechanism(s) by which FTO post-transcriptionally regulates expression of its direct target genes, followed by functional studies of the top candidate targets of FTO in the pathogenesis of FTO-high AMLs. 3) We will use both mouse BMT leukemia models and patient- derived xeno-transplantation models to determine the role and underlying molecular mechanism of FTO in the response of FTO-high AMLs to ATRA and/or ATO treatment. The critical target genes of FTO and relevant pathways that are responsible for the response of FTO-high AMLs to ATRA and/or ATO treatment will be identified.
The major goal of this proposal is to investigate the role and underlying mechanism of FTO, a major N6- methyladenosine (m6A) demethylase (?eraser?), in the pathogenesis and drug response of various major subtypes of acute myeloid leukemias (AMLs; one of the most common and fatal types of hematopoietic malignancies) that have a relatively high abundance of FTO expression. Thus, the success of this project will provide profound novel insights into the biological functions of m6A modification and the critical components of the m6A machineries (e.g., FTO) in leukemogenesis and drug response, and may also lead to the development of novel therapeutic strategies to treat such AMLs. Therefore, our project is of great significance in both basic research and translational research.
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