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 突变克隆造血中致癌炎症所必需的


TET2 突变 （mTET2） 是髓系恶性肿瘤和克隆性造血 （CH） 中的常见遗传事件。这些突变出现在起始克隆中，并与许多与致癌前馈炎症回路相关的临床后遗症有关。然而，负责增强这种炎症回路的 mTET2 的直接下游效应子尚不清楚。为了解决这个问题，我们在有和没有 TET2 突变 CH 的 COVID-19 患者中进行了 scRNA 和 scATAC-seq，理由是 COVID-19 的炎症可能突出了 mTET2 的关键下游转录靶点。使用这种方法，我们确定了 MALAT1，一种治疗上可处理的 lncRNA，作为 mTET2 的中央下游效应子，对于在体内诱导 mTET2 的致癌促炎特征既必要又充分。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，这导致 RNA“屏蔽”PP2A 去磷酸化，从而阻止炎症信号的解决。