Targeting the stem cell niche in the myeloid malignancies
S Méndez Ferrer(1)
1:University of Cambridge and NHS Blood and Transplant; 2:On behalf of TAMARIN co-investigators
Haematopoietic stem cells (HSCs) reside in specialised niches that allow them to self-renew, proliferate, differentiate and migrate according to the organism's requirements. Our previous work showed that the brain regulates a peripheral stem cell niche in the bone marrow (Nature 452:442; Blood 133:224; Nat Comms 13:543), where mesenchymal stem cells (MSCs) play a key role in the normal HSC niche (Nature 466:829). Ageing is associated with an increased risk to develop myeloid malignancies, such as myeloproliferative neoplasms (MPNs) and acute myeloid leukaemia (AML). Our recent work showed that remodelling of bone marrow niches promotes myeloid cell expansion during premature or physiological ageing (Cell Stem Cell 25:407). Furthermore, AML cells co-opt energy sources and antioxidant defence mechanisms from HSC niche-forming MSCs to survive chemotherapy (Cell Metab 32:829), suggesting that adjuvant niche-targeting therapies could be therapeutic (Nat Rev Cancer 20:285). Indeed, damage to the HSC niche regulation is required for MPN progression (Nature 512:78). Along this line, the neuroendocrine regulation of bone marrow stem cells by noradrenergic signals (Haematologica 104:710) or by sex hormones (Cell Stem Cell 15:971) could potentially be harnessed to offer novel therapeutic approaches in MPN. The latter has been recently tested in a Phase II, multicentre, single arm clinical trial assessing tamoxifen’s safety and activity in reducing molecular markers of disease burden in MPN (TAMARIN). The results suggest that tamoxifen can modulate unfolded protein response and inhibit mitochondrial respiration and pathogenic JAK-STAT signalling in a subset of potentially prospectively identifiable patients.