RNA Shielding of p65 Is Required to Potentiate Oncogenic Inflammation in TET2-Mutated Clonal Hematopoiesis.

IF 29.7 1区医学 Q1 ONCOLOGY

Cancer discovery Pub Date : 2024-12-02 DOI:10.1158/2159-8290.CD-24-0093

Nana Adjoa Ben-Crentsil, Wazim Mohammed Ismail, Maria E Balasis, Hannah Newman, Ariel Quintana, Moritz Binder, Traci Kruer, Surendra Neupane, Meghan C Ferrall-Fairbanks, Jenna Fernandez, Terra L Lasho, Christy M Finke, Mohammed L Ibrahim, Kathy L McGraw, Michael Wysota, Amy L Aldrich, Christopher B Ryder, Christopher T Letson, Joshua Traina, Amy F McLemore, Nathalie Droin, Aditi Shastri, Seongseok Yun, Eric Solary, David A Sallman, Amer A Beg, Li Ma, Alexandre Gaspar-Maia, Mrinal M Patnaik, Eric Padron

引用次数: 0

Abstract

Significance: This work identifies MALAT1 as a requisite downstream effector of oncogenic feedforward inflammatory circuits necessary for the development of TET2-mutated CH and fulminant myeloid malignancy. We elucidate a novel mechanism by which MALAT1 "shields" p65 from dephosphorylation to potentiate this circuit and nominate MALAT1 inhibition as a future therapeutic strategy.

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在 TET2 突变的克隆造血过程中，需要 P65 的 RNA 屏蔽来增强致癌炎症。

TET2突变（mTET2）是髓系恶性肿瘤和克隆性造血（CH）中常见的遗传事件。这些突变发生在创始克隆中，与许多与致癌前馈炎症回路相关的临床后遗症有牵连。然而，mTET2 的直接下游效应器对这种炎症回路的增效作用尚不清楚。为了解决这个问题，我们在有或没有 TET2 基因突变的 COVID-19 患者中进行了 scRNA 和 scATAC-seq，理由是 COVID-19 引起的炎症可能会突出 mTET2 的关键下游转录靶标。利用这种方法，我们确定了可用于治疗的 lncRNA MALAT1，它是 mTET2 的核心下游效应物，对于诱导 mTET2 在体内的致癌促炎特征是必要且充分的。我们还阐明了 mTET2 上调 MALAT1 的机制，并描述了 MALAT1 与 P65 之间的相互作用，这种相互作用会导致 RNA "屏蔽 "PP2A 的去磷酸化，从而阻止炎症信号的传递。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cancer discovery ONCOLOGY-

CiteScore

22.90

自引率

1.40%

发文量

838

审稿时长

6-12 weeks

期刊介绍： Cancer Discovery publishes high-impact, peer-reviewed articles detailing significant advances in both research and clinical trials. Serving as a premier cancer information resource, the journal also features Review Articles, Perspectives, Commentaries, News stories, and Research Watch summaries to keep readers abreast of the latest findings in the field. Covering a wide range of topics, from laboratory research to clinical trials and epidemiologic studies, Cancer Discovery spans the entire spectrum of cancer research and medicine.