TET2 mutations (mTET2) are common genetic events in myeloid malignancies and clonal hematopoiesis (CH). These mutations arise in the founding clone and are implicated in many clinical sequelae associated with oncogenic feedforward inflammatory circuits. However, the direct downstream effector of mTET2 responsible for the potentiation of this inflammatory circuit is unknown. To address this, we performed scRNA and scATAC-seq in COVID-19 patients with and without TET2-mutated CH reasoning that the inflammation from COVID-19 may highlight critical downstream transcriptional targets of mTET2. Using this approach, we identified MALAT1, a therapeutically tractable lncRNA, as a central downstream effector of mTET2 that is both necessary and sufficient to induce the oncogenic pro-inflammatory features of mTET2 in vivo. We also elucidate the mechanism by which mTET2 upregulate MALAT1 and describe an interaction between MALAT1 and P65 which leads to RNA “shielding” from PP2A dephosphorylation thus preventing resolution of inflammatory signaling.

中文翻译：

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P65 的 RNA 屏蔽是增强 TET2 突变克隆造血过程中致癌炎症所必需的


TET2 突变 (mTET2) 是骨髓恶性肿瘤和克隆造血 (CH) 中常见的遗传事件。这些突变出现在创始克隆中，并涉及许多与致癌前馈炎症回路相关的临床后遗症。然而，mTET2 负责增强这种炎症回路的直接下游效应器尚不清楚。为了解决这个问题，我们对有或没有 TET2 突变的 CH 的 COVID-19 患者进行了 scRNA 和 scATAC-seq，推理出 COVID-19 引起的炎症可能会突出 mTET2 的关键下游转录靶标。使用这种方法，我们确定了 MALAT1（一种治疗上易于处理的 lncRNA）作为 mTET2 的中央下游效应子，对于在体内诱导 mTET2 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 和 P65 之间的相互作用，这种相互作用导致 RNA“屏蔽”PP2A 去磷酸化，从而阻止炎症信号传导的解决。