Fig. 2. Potential pathophysiological models. (A) In this model, AML and MDS originate from a primary stromal defect. Functional alterations of MSPCs result in genotoxic stress and dysregulated crosstalk with HSPC favouring the acquisition of genetic and molecular aberrations. This supports the establishment and expansion of clonal hematopoiesis. (B) In this model, AML and MDS originate from primary alterations of the HSPC compartment. In a second step these clonal hematopoietic cells induce phenotypic and functional changes in the BM microenvironment turning it into a self-reinforcing niche, which supports malignant cells at the expense of healthy hematopoiesis.

Abbreviations: CCL3, Chemokine (C-C motif) ligand 3; ECM, extracellular matrix; G-CSF, Granulocyte-colony stimulating factor; HSC, hematopoietic stem and progenitor cells; MSCP, mesenchymal stem and progenitor cell; ROS, reactive oxygen species; TGF-β, transforming growth factor-beta; TPO, thrombopoietin.