Loss of SIMPL compromises TNF-α-dependent survival of hematopoietic progenitors

ObjectiveEmerging work has revealed an integral role of the tumor necrosis factor–α (TNF-α) nuclear factor (NF)-κB pathway in the regulation of hematopoiesis. TNF-α inhibition of hematopoietic stem/progenitor cell growth involves type I TNF-α receptor (TNF-RI) and type II TNF-α receptor (TNF-RII). However, the role of TNF-RI vs TNF-RII in mediating this response is less clear. Full induction of NF-κB–dependent gene expression through TNF-RI requires the transcriptional coactivator SIMPL (substrate that interacts with mouse pelle-like kinase). To address the role of SIMPL in TNF-α-dependent signaling in hematopoiesis, endothelial cells and hematopoietic progenitors expressing SIMPL short hairpin RNA were characterized.Material and MethodsIn vitro gene expression and progenitor assays employing SIMPL short hairpin RNA were used to examine the requirement for SIMPL in TNF-α–dependent effects upon cytokine gene expression and hematopoietic progenitor cell growth. Competitive repopulation studies were used to extend these studies in vivo.ResultsSIMPL is required for full TNF-RI–dependent expression of NF-κB–controlled cytokines in endothelial cells. Hematopoietic progenitor cell expansion is not affected if progenitors lacked SIMPL or if progenitors are treated with human TNF-α, which signals through TNF-RI. In the absence of SIMPL, human TNF-α leads to a dramatic decrease in progenitor cell expansion that is not due to apoptosis. Loss of SIMPL does not affect the activity of transforming growth factor–β1 and interferon-γ, other known suppressors of hematopoiesis.ConclusionsSuppression of myeloid progenitor cell expansion requires signaling through TNF-RI and TNF-RII. Signals transduced through the TNF-α–TNF-RI–SIMPL pathway support hematopoietic progenitor cell survival, growth and differentiation.