The Novel Role and Mechanism of RBM33 in Leukemogenesis

RBM33 在白血病发生中的新作用和机制

基本信息

  • 批准号:
    10343898
  • 负责人:
  • 金额:
    $ 40.6万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-05-17 至 2027-03-31
  • 项目状态:
    未结题

项目摘要

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.
摘要

项目成果

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Zhijian Qian其他文献

Zhijian Qian的其他文献

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{{ truncateString('Zhijian Qian', 18)}}的其他基金

The role of ALKBH5-mediated RNA demethylation in the maintenance of genomic stability in HSPCs
ALKBH5 介导的 RNA 去甲基化在维持 HSPC 基因组稳定性中的作用
  • 批准号:
    10445661
  • 财政年份:
    2022
  • 资助金额:
    $ 40.6万
  • 项目类别:
Role of the TET1 short isoform in MDS development and maintenance
TET1 短亚型在 MDS 开发和维护中的作用
  • 批准号:
    10363322
  • 财政年份:
    2022
  • 资助金额:
    $ 40.6万
  • 项目类别:
The role of ALKBH5-mediated RNA demethylation in the maintenance of genomic stability in HSPCs
ALKBH5 介导的 RNA 去甲基化在维持 HSPC 基因组稳定性中的作用
  • 批准号:
    10669161
  • 财政年份:
    2022
  • 资助金额:
    $ 40.6万
  • 项目类别:
The role of YTHDC1 in normal and malignant hematopoiesis
YTHDC1在正常和恶性造血中的作用
  • 批准号:
    10620127
  • 财政年份:
    2022
  • 资助金额:
    $ 40.6万
  • 项目类别:
The Novel Role and Mechanism of RBM33 in Leukemogenesis
RBM33 在白血病发生中的新作用和机制
  • 批准号:
    10623163
  • 财政年份:
    2022
  • 资助金额:
    $ 40.6万
  • 项目类别:
Role of the TET1 short isoform in MDS development and maintenance
TET1 短亚型在 MDS 开发和维护中的作用
  • 批准号:
    10552668
  • 财政年份:
    2022
  • 资助金额:
    $ 40.6万
  • 项目类别:
The role of YTHDC1 in normal and malignant hematopoiesis
YTHDC1在正常和恶性造血中的作用
  • 批准号:
    10361997
  • 财政年份:
    2022
  • 资助金额:
    $ 40.6万
  • 项目类别:
The role of ALKBH5-mediated RNA demethylation in the maintenance of genomic stability in HSPCs
ALKBH5 介导的 RNA 去甲基化在维持 HSPC 基因组稳定性中的作用
  • 批准号:
    10476005
  • 财政年份:
    2021
  • 资助金额:
    $ 40.6万
  • 项目类别:
The molecular mechanism of clonal dominance in 5q(del) MDS
5q(del)MDS克隆优势的分子机制
  • 批准号:
    9795448
  • 财政年份:
    2019
  • 资助金额:
    $ 40.6万
  • 项目类别:
The molecular mechanism of clonal dominance in 5q(del) MDS
5q(del)MDS克隆优势的分子机制
  • 批准号:
    9312796
  • 财政年份:
    2016
  • 资助金额:
    $ 40.6万
  • 项目类别:

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