Inhibition of Inflammatory Signaling in Tet2 Mutant Preleukemic Cells Mitigates Stress-Induced Abnormalities and Clonal Hematopoiesis

Abstract

<p id="P3">Inflammation is a risk factor for cancer development. Individuals with preleukemic <i>TET2</i> mutations manifest clonal hematopoiesis and are at a higher risk of developing leukemia. How inflammatory signals influence the survival of preleukemic hematopoietic stem and progenitor cells (preleukemic-HSPCs) is unclear. We show a rapid increase in the frequency and absolute number of <i>Tet2</i>-KO mature myeloid cells and HSPCs in response to inflammatory stress, which results in enhanced production of inflammatory cytokines, including IL-6, and resistance to apoptosis. IL-6 induces hyperactivation of the Shp2-Stat3 signaling axis, resulting in increased expression of a novel anti-apoptotic lncRNA, <i>Morrbid</i>, in <i>Tet2</i>-KO myeloid cells and HSPCs. Expression of activated Shp2 in HSPCs phenocopies <i>Tet2</i> loss, with regard to hyperactivation of Stat3 and <i>Morrbid</i>. <i>In vivo</i>, pharmacologic inhibition of Shp2 or Stat3 or genetic loss of <i>Morrbid</i> in <i>Tet2</i>-mutant mice rescues inflammatory stress-induced abnormalities in HSPCs and mature myeloid cells including clonal hematopoiesis. </p><p id="P4">Cai <i>et al</i> report that Tet2-deficient hematopoietic stem and progenitor cells manifest hyperactive IL-6/Shp2/Stat3/ <i>Morrbid</i> pathway, which promotes cell survival under basal conditions as well as in response to inflammatory stress. Blocking this pathway using anti-inflammatory drugs E3330 and SHP099 or by genetic loss of <i>Morrbid</i> mitigates this response. </p><p id="P5"> <div class="figure-container so-text-align-c"> <img alt="" class="figure" src="/document_file/536a368e-c69d-489c-8954-60f9fb7e9abc/PubMedCentral/image/nihms-1512207-f0001.jpg"/> </div> </p>