Cytokine-mediated regulation of normal and neoplastic hematopoietic stem cells by natural killer cells

Abstract

Considering that hematopoietic stem cells (HSC) directly respond to cytokines like IFNg, TNFa, TGFb, GM-CSF, MIP1, IL-10 and others, we hypothesized that Natural Killer (NK)-mediated cytokine production could regulate HSC function (subproject 1) and that its deregulation may favor malignant transformation (subproject 2). To address the role of NK function in normal hematopoiesis, we will co-cultivate wild type (wt) and Cebpg KO deficient NK cells and normal HSCs and asses the effects of NK cells on HSC's proliferation and hematological reconstitution potential. We plan to investigatee the mechanisms involved in such regulation by the use of gene expression and cytokine profile assays of NK cells. In the second part of the project, we plan to study the regulation of myeloproliferative neoplasms (MPN) stem cells by NK cell activity by the use of a conditional knockin Jak2V617F mutation (Jak2VF) murine model, which faithfully resemble the main clinical and laboratorial characteristics of human Polycythemia Vera. We recently found that Jak2VF mice have lower numbers of NK cells as compared to controls and aim to study the immunophenotype, receptor activation, cytokine profile and function of the Jak2VF NK subset. To further characterize NK activity in this model, we intend to co-culture Jak2WT and Jak2VF NK cells with HSCs and evaluate its proliferation, differentiation and self-renewal properties. In summary, with this proposal, we intend to study the interplay between HSCs and NK cells, that may collaborate in the task of regulating the normal and malignant hematopoiesis, aiming to identify new therapeutic targets that may regulate this complex interaction. (AU)