Pérdida de TET2 mejora la respuesta temprana a la inflamación en células mieloides primitivas y comprometidas

In vivo IL-1β exposure elicits enhanced hematopoietic stem cell (HSC) self-renewal and myeloid priming in Tet2^KO mice, but information on how Tet2^KO affects the early transcriptional response to IL-1β is lacking. To address this, we used an inducible, in vitro model of myeloid differentiation coupled with RNA-sequencing (RNAseq) to study the effects of Tet2^KO on short-term IL-1β stimulation. In both Tet2^KO progenitor and differentiated states, we identified baseline increases in expression of several cytokine signaling receptors, including Il1r1, as well as increases in inflammasome components. Interaction effect modeling revealed that loss of TET2 and IL-1β stimulation collaborate, leading to significant increases in both inflammatory cytokine expression and regulators of proliferation and differentiation in the progenitor state, and elevated cytokine production in differentiated cells. We then show that IKK-complex inhibition prevents both the IL-1β-induced proliferation of Tet2^KO progenitors and TNFα production in differentiated myeloid cells, highlighting a potential therapeutic target in TET2-deficient cells. Teaser Abstract: TET2 loss and IL-1β stimulation collaborate to induce cytokine expression as well as proliferation and differentiation related transcription factors in myeloid progenitors, while differentiated myeloid cells lacking TET2 produce a much larger, more diverse repertoire of inflammatory cytokine transcripts. Both of these cell-state specific effects of TET2 loss were countered with IKK-complex inhibition, highlighting a potential therapeutic avenue for clonal blood disorders.