Assessing the Interplay Between Inflammatory Signaling and Epigenetic Dysregulation in Age-associated Clonal Hematopoiesis and Leukemia Initiation

评估炎症信号传导与表观遗传失调在年龄相关克隆造血和白血病起始中的相互作用

基本信息

  • 批准号:
    10659254
  • 负责人:
  • 金额:
    $ 51.55万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-09-15 至 2026-06-30
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY/ABSTRACT Age is one of the most clearly defined risk factors for cancer. As the incidence of cancer increases with age, rising more rapidly beginning in mid-life (ages 45-64 years), cancer can be considered an age-related disease. Recent studies have identified age-dependent somatic mutations, including alleles with a role in cancer initiation, in a spectrum of human tissues. In the hematopoietic system this is termed clonal hematopoiesis (CH) and is most commonly caused by mutations in the epigenetic regulators DNMT3A, TET2, and ASXL1 within the hematopoietic stem and progenitor cell (HSPC) compartment. How the aging process promotes clonal selection, expansion, and transformation from CH to acute myeloid leukemia (AML) is poorly understood. The long-term goal of this research is to understand the mechanisms by which aging promotes transformation causing hematologic malignancies. The overall objective of this proposal is to elucidate the mechanisms by which increased inflammation observed during aging promotes expansion of CH-mutant HSPCs, and the extent to which this fitness advantage is provided by altered epigenetic regulation occurring as a direct consequence of CH mutations. Preliminary data show that CH-mutant HSPCs have a more potent selective advantage and undergo more rapid malignant transformation in aged compared to young mice. Mechanistically, increased inflammation in aged mice is a driver of this phenotype and epigenetic alterations are found to accumulate in CH-mutant HSPCs with aging. These data support the central hypothesis that aging-associated inflammation is a selective pressure favoring CH-mutant HSPC expansion and malignant transformation, and that clonal expansion, epigenetic alterations, and risk of transformation caused by CH mutations are dependent upon sustained CH-mutant allele expression. This project will use cellular and molecular biological approaches in aged mice integrated with studies using primary human CH samples to achieve the following specific aims: AIM 1. Determine the extent to which clonal hematopoietic expansion and leukemic transformation in the aging context is due to inflammation; and AIM 2. Determine the mechanisms by which, and extent to which, reversion of a CH mutation during aging alters clonal evolution and risk of leukemia initiation. The proposed research is conceptually innovative because it is the first to determine how inflammation and epigenetic dysregulation conspire during the aging process to expand, evolve and transform CH-mutant clones. The proposed research is technically innovative as it incorporates novel co-culture systems and therapeutic studies to assess key inflammatory drivers, as well as a novel murine model with CH-mutant induction and reversion capabilities to investigate CH mutant allele dependencies in clonal expansion, epigenetic alterations, and leukemic transformation. This study is significant because understanding the mechanisms by which aging contributes to clonal expansion and transformation will provide insights into effective therapeutic strategies targeting clonal evolution, attenuate pathophysiology promoted by clonal expansion, and intercept malignant transformation.
项目总结/文摘

项目成果

期刊论文数量(0)
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会议论文数量(0)
专利数量(0)

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Ross L Levine其他文献

Blood flow reactivity to hypercapnia in strictly unilateral carotid disease: preliminary results.
严格单侧颈动脉疾病中血流对高碳酸血症的反应:初步结果。
  • DOI:
  • 发表时间:
    1991
  • 期刊:
  • 影响因子:
    11
  • 作者:
    Ross L Levine;Jeffrey A Dobkin;JackM Rozental;Martin R Satter;R. J. Nickles;William S Middleton
  • 通讯作者:
    William S Middleton
Crebbp Inhibition Potentiates JAK2 Inhibition in Post-MPN Acute Myeloid Leukemia
  • DOI:
    10.1182/blood-2024-201988
  • 发表时间:
    2024-11-05
  • 期刊:
  • 影响因子:
  • 作者:
    Kalay Bertulfo;Hannah Miller;Ryan Najac;Juan Carlos Castelan;Cindy Ma;Koen Debackere;Wenbin Xiao;Raajit Rampal;Ross L Levine;Chao Lu;Adolfo A. Ferrando;Teresa Palomero
  • 通讯作者:
    Teresa Palomero
TMPRSS6 Antisense Oligonucleotide Therapy Reverses Inflammation in <em>Jak2</em><sup>V617F</sup> Mutant Mice
  • DOI:
    10.1182/blood-2024-203806
  • 发表时间:
    2024-11-05
  • 期刊:
  • 影响因子:
  • 作者:
    Maayan Levy;Huihui Li;Andrew Dunbar;Zixing Huang;Young Park;Min Lu;Pinanong Na Phattalung;Marina Planoutene;Carla Casu;Stefano Rivella;Shuling Guo;Ross L Levine;Ronald Hoffman;Yelena Ginzburg
  • 通讯作者:
    Yelena Ginzburg
TET2 and TP53 Mutations Cooperate in Leukemia Development and Modulate the Response to Inflammation
  • DOI:
    10.1182/blood-2024-202521
  • 发表时间:
    2024-11-05
  • 期刊:
  • 影响因子:
  • 作者:
    Pablo Sanchez Vela;Brianna Kelly;Claudia Brady;Jonathan Foox;Jacob Glass;Ross L Levine;Alan Shih
  • 通讯作者:
    Alan Shih
A Phase 1b Multi-Center Study of the FLT3 Inhibitor Gilteritinib in Combination with the IDH1 Inhibitor Ivosidenib or the IDH2 Inhibitor Enasidenib for Patients with Relapsed or Refractory Acute Myeloid Leukemia Who Have Co-Occurring FLT3/IDH1 or FLT3/IDH2 Mutations
  • DOI:
    10.1182/blood-2023-190801
  • 发表时间:
    2023-11-02
  • 期刊:
  • 影响因子:
  • 作者:
    Eytan M. Stein;Andriy Derkach;Gabrielle Melamed;Alana Block;Janet Kim;Gergana Georgieva;Vanessa Thompson;Ross L Levine;Andrew M. Intlekofer;Omar Abdel-Wahab;Martin S. Tallman
  • 通讯作者:
    Martin S. Tallman

Ross L Levine的其他文献

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{{ truncateString('Ross L Levine', 18)}}的其他基金

Assessing the Interplay Between Inflammatory Signaling and Epigenetic Dysregulation in Age-associated Clonal Hematopoiesis and Leukemia Initiation
评估炎症信号传导与表观遗传失调在年龄相关克隆造血和白血病起始中的相互作用
  • 批准号:
    10291637
  • 财政年份:
    2021
  • 资助金额:
    $ 51.55万
  • 项目类别:
Assessing the Interplay Between Inflammatory Signaling and Epigenetic Dysregulation in Age-associated Clonal Hematopoiesis and Leukemia Initiation
评估炎症信号传导与表观遗传失调在年龄相关克隆造血和白血病起始中的相互作用
  • 批准号:
    10488271
  • 财政年份:
    2021
  • 资助金额:
    $ 51.55万
  • 项目类别:
Developmental Research Program
发展研究计划
  • 批准号:
    10474305
  • 财政年份:
    2021
  • 资助金额:
    $ 51.55万
  • 项目类别:
Project 1: Increasing therapeutic efficacy in isocitrate dehydrongenase (IDH)–mutant acute myeloid leukemia (AML)
项目1:提高异柠檬酸脱氢酶(IDH)突变型急性髓系白血病(AML)的治疗效果
  • 批准号:
    10474275
  • 财政年份:
    2021
  • 资助金额:
    $ 51.55万
  • 项目类别:
Synergistic role of signaling and epigenetics in leukemic transformation
信号传导和表观遗传学在白血病转化中的协同作用
  • 批准号:
    10323022
  • 财政年份:
    2017
  • 资助金额:
    $ 51.55万
  • 项目类别:
Synergistic role of signaling and epigenetics in leukemic transformation
信号传导和表观遗传学在白血病转化中的协同作用
  • 批准号:
    10543794
  • 财政年份:
    2017
  • 资助金额:
    $ 51.55万
  • 项目类别:
Synergistic role of signaling and epigenetics in leukemic transformation
信号传导和表观遗传学在白血病转化中的协同作用
  • 批准号:
    10737736
  • 财政年份:
    2017
  • 资助金额:
    $ 51.55万
  • 项目类别:
Synergistic role of signaling and epigenetics in leukemic transformation
信号传导和表观遗传学在白血病转化中的协同作用
  • 批准号:
    10078940
  • 财政年份:
    2017
  • 资助金额:
    $ 51.55万
  • 项目类别:
ECOG-ACRIN INTEGRATED LEUKEMIA TRANSLATIONAL RESEARCH CENTER
ECOG-ACRIN 综合白血病转化研究中心
  • 批准号:
    9235262
  • 财政年份:
    2014
  • 资助金额:
    $ 51.55万
  • 项目类别:
ECOG-ACRIN INTEGRATED LEUKEMIA TRANSLATIONAL RESEARCH CENTER
ECOG-ACRIN 综合白血病转化研究中心
  • 批准号:
    9031084
  • 财政年份:
    2014
  • 资助金额:
    $ 51.55万
  • 项目类别:

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