In acute myeloid leukaemia (AML) the suppression of haematopoietic stem and progenitor cell (HSPC) differentiation and proliferation is a major factor contributing to treatment complications and mortality rates. Previous studies associated an altered microenvironment with dysregulated haematopoiesis but the precise molecular mechanisms are still not fully understood.

To mimic AML infiltrated human bone marrow (BM), we utilised our published humanised 3D BM model. Healthy donor MSCs were cultured on a 3D collagen scaffold, co-injected with normal CD34+ HSPCs with AML and transplanted into NSG-SGM3 mice. In analogue, we co-cultured healthy BM MSCs with HSPCs and AML.

Both ex vivo and in vivo models replicated a suppression of normal haematopoiesis. Similar to AML patients, cell death was affected minimally but the majority of HSPCs were quiescent and showed an enrichment of serial colony-forming cells and LTC-ICs.
Ex vivo, HSPC suppression was largely dependent on the presence of MSCs but not in a direct contact manner. Stroma secretome analysis identified the previously uncharacterized stanniocalcin-1 (STC1). STC1 is exclusively expressed in MSCs and upregulated 2 to 30-fold after AML contact. Supplemented recombinant STC1 significantly enriches for quiescent HSPCs and helps to preserve their functionality, while the proliferation of AML was unchanged. Neutralisation of STC1 in AML scaffolds improved HSPC cell number through increased proliferation.
Further transcriptomic interrogation of the MSCs after AML exposure also identified an upregulation of Hypoxia-inducible factor -1 alpha (HIF-1α) target genes and increased stabilisation of HIF-1α. Knockdown of HIF-1α in MSCs not only abrogates secreted STC1 but also improves HSPC proliferation in the presence of AML.

In conclusion, the newly developed humanised ex vivo and in vivo models mimic the suppression of HSPCs by AML but are dependent on an altered MSC niche and the HIF-1α-STC1 axis. Inhibition of niche remodelling may be an interesting new approach to improve recovery after AML treatment.