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Principal Investigator: Zhijian Qian
Organization: UNIVERSITY OF FLORIDA
Fiscal Year: 2024
Award: $385,748
Funding agency: National Cancer Institute
Abstract
Acute myeloid leukemia (AML) is one of the most common and fatal forms of hematological malignancies
caused by gene mutations and genomic rearrangements. The cure rates for AML patients have not
significantly improved for decades. The molecular mechanisms underlying the pathogenesis of AML are not
fully understood. By analysis of publicly available genomic data using a new machine learning approach, RNA
Binding Motif Protein 33 (RBM33), an RNA binding protein, is identified as an essential gene in AML.
However, the biological function of RBM33 is unknown yet. Our preliminary studies provide the first compelling
evidence suggesting a novel function of RBM33 in regulating m6A RNA demethylation. More importantly, we
showed that RBM33 knockdown significantly inhibited growth and survival of human and mouse leukemia
cells. At a molecular level, we have identified a potential downstream target of RBM33 in leukemia cells.
ALKBH5 is known as an m6A mRNA demethylase (Eraser), which removes m6A methylated groups from RNA.
To date, it remains unknown whether another member of RNA binding proteins is required for ensuring
recruitment of ALKBH5 to its mRNA targets. We have recently demonstrated that ALKBH5 has a critical role in
AML development and maintenance. We hypothesize that RBM33 plays a critical role in the pathogenesis of
AML by regulating ALKBH5-mediated m6A demethylation. To test this hypothesis, we will pursue three specific
aims. In Aim1, we will determine a novel role of RBM33 in regulation of dynamic m6A RNA methylation in
leukemia cells. In Aim2, we will investigate the role of Rbm33 in AML development and maintenance. In Aim 3,
we will determine the downstream pathway that mediates the function of RBM33 in leukemogenesis in AML.
We will employ both mouse genetic models as well as human patient-derived mouse models to elucidate the
role of RBM33 in normal hematopoiesis and leukemogenesis in vivo, and will combine transcriptome and
epitranscriptome analysis to identify the key downstream targets and associated downstream pathways that
mediate the role of RBM33 in leukemogenesis. Our studies will uncover a novel role of RBM33 in m6A RNA
modification, and define the importance and underlying mechanisms of RBM33 in AML development and
maintenance as well as LSC/LIC self-renewal. Thus, the success of our project will significantly advance our
understanding of the complex mechanisms underlying the m6A modification-mediated gene regulation in
leukemia cells and the critical role of m6A RNA demethylation in leukemogenesis.
Terms: <AML - Acute Myeloid Leukemia><Acute Myeloblastic Leukemia><Acute Myelocytic Leukemia><Acute Myelogenous Leukemia><Binding><Binding Sites><Biological Function><Biological Process><Blood Precursor Cell><CLIP-Seq><Cancer Genes><Cancer-Promoting Gene><Cell Body><Cells><Combining Site><Complex><DNA Sequence Rearrangement><Data><Dependence><Development><ERIC1><Ensure><Essential Genes><Gene Action Regulation><Gene Alteration><Gene Expression><Gene Expression Regulation><Gene Mutation><Gene Regulation><Gene Regulation Process><Generalized Growth><Genes><Genetic Models><Genomic approach><Growth><HITS-CLIP><Hematologic Cancer><Hematologic Malignancies><Hematologic Neoplasms><Hematological Malignancies><Hematological Neoplasms><Hematological Tumor><Hematopoiesis><Hematopoietic Cancer><Hematopoietic Cellular Control Mechanisms><Hematopoietic Progenitor Cells><Hematopoietic stem cells><High-throughput sequencing of CLIP cDNA library><Human><Leukemic Cell><Leukemic progenitor and stem cell><Machine Learning><Maintenance><Malignant Hematologic Neoplasm><Maps><Mediating><Messenger RNA><Methylation><Mice><Mice Mammals><Modern Man><Modification><Molecular><Molecular Interaction><Murine><Mus><Non-Polyadenylated RNA><Oncogenes><Pathogenesis><Pathogenicity><Pathway interactions><Patients><Play><Polyribosomes><Polysomes><Post-Transcriptional Control><Post-Transcriptional Regulation><Protein Binding Domain><Protein Binding Motif><Protein-Protein Interaction Domain><Proteomics><RNA><RNA Binding><RNA Gene Products><RNA Seq><RNA bound><RNA methylation><RNA sequencing><RNA-Binding Proteins><RNAseq><Reactive Site><Reader><Regulation><Ribonucleic Acid><Ribosomes><Role><Site><TACC3><TACC3 gene><Testing><Tissue Growth><Transcript><Transforming Genes><acute granulocytic leukemia><acute myeloid leukemia><blood cell formation><blood cell progenitor><blood progenitor><blood stem cell><blood-forming stem cell><crosslinking and immunoprecipitation sequencing><demethylation><developmental><epitranscriptome><genomic data><genomic data-set><genomic dataset><genomic effort><genomic rearrangement><genomic strategy><global gene expression><global transcription profile><hematopoietic progenitor><hematopoietic stem progenitor cell><hemopoietic progenitor><hemopoietic stem cell><improved><in vivo><knock-down><knockdown><leukemia><leukemia treatment><leukemic progenitor><leukemic stem cell><leukemic therapy><leukemogenesis><mRNA><machine based learning><member><mouse genetics><mouse model><murine model><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><novel><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><ontogeny><pathway><post-transcriptional gene regulation><posttranscriptional><posttranscriptional control><posttranscriptional regulation><progenitor cell regeneration><progenitor cell self renewal><progenitor regeneration><progenitor self renewal><recruit><self-renew><self-renewal><social role><stem><stem and progenitor cell regeneration><stem and progenitor cell self renewal><stem cell regeneration><stem cell self renewal><success><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><transcriptome><transcriptome sequencing><transcriptomic sequencing>