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

Menée à l'aide de lignées cellulaires, de modèles murins ainsi que d'échantillons sanguins et d'échantillons de moelle osseuse prélevés sur des patients présentant un syndrome myélodysplasique ou atteints de la COVID-19, cette étude identifie un mécanisme par lequel la mutation du gène TET2 (gène codant pour la méthylcytosine dioxygénase) favorise le renforcement de l'ARN de la protéine P65 via la synthèse du transcrit MALAT1 et accentue le processus inflammatoire oncogène lors de l'hématopoïèse clonale

Résumé en anglais

TET2 mutations (mTET2) are common genetic events in myeloid malignancies and clonal hematopoiesis. 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 these inflammatory circuits is unknown. To address this, we performed scRNA-seq and scATAC-seq in patients with COVID-19 with and without TET2-mutated clonal hematopoiesis reasoning that inflammation from COVID-19 may highlight critical downstream transcriptional targets of mTET2. Using this approach, we identified metastasis-associated lung adenoma transcript 1 (MALAT1), a therapeutically tractable lncRNA, as a central downstream effector of mTET2 that is both necessary and sufficient to induce the oncogenic proinflammatory 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 protein phosphatase 2A dephosphorylation, thus preventing resolution of inflammatory signaling.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.