Understanding instructive cytokine signalling in preleukaemic haematopoietic stem cells

Haematopoietic stem cells (HSCs) differentiate into mature blood cells through the control of multiple cytokines at various branch points and HSCs are capable of adjusting haematopoiesis in response to different physiological triggers. In many patients with a range of myeloid malignancies, loss of function TET2 mutations have frequently been observed. TET2 has been found to be a critical regulator of self-renewal and differentiation of HSCs and many of the responses of HSCs to cytokines have been shown to be impacted by TET2 mutations. We sought to study the cytokine response of wildtype and TET2 mutated HSCs to gain insight into whether specific pathways might contribute to explaining the differing cell fates between mutant and non-mutant HSCs. We found that TET2+/- HSCs are hyporesponsive to IL-4 and exhibit slower cell cycle kinetics in response to IL-4, IFN-γ, TGF-β and IL-6. We also demonstrated that IL-6 and TGF-β promote differentiation of TET2+/- HSCs and TET2+/- HSCs produce fewer granulocytes in response to TGF-β. In addition, our data showed that TET2+/- HSCs do not demonstrate reduced colony forming efficiency in response to IL-4 and IFN-γ. It was also noticed, through this project, that TET2+/- untreated cultures have elevated Sca-1 expression which highlights the emergence of a hyperinflammatory state in myeloid malignancies with TET2 mutations such as AML. Further research will be necessary to explain the reasons why many of these differential cell fate decisions occur.