BM microenvironment presenting the HSC niche. The HSC niche is composed mainly of perivascular MSPCs and endothelial cells. They are producing CXCL12 and SCF required for HSC maintenance and retention in BM. BM endothelial cells expressing specific adhesion molecules (e.g. E-selectin) assist homing and engraftment of HSCs. CAR cells regulate both lymphoid progenitor maturation and myeloid progenitor retention. Sympathetic neuronal cells that innervate arterioles regulates HSC mobilization through circadian release of noradrenaline, which modulates CXCL12 expression. ECMs and other cells including macrophage, megakaryocyte, and osteoprogenitor cells are also participating in this landscape. Abbreviations: BM, bone marrow; ECM, extracellular matrix; HSC, hematopoietic stem cell; MSCP, mesenchymal stem and progenitor cell; SCF, stem cell factor; TGF-β1, transforming growth factor beta-1; CAR cell, CXCL12-abundant reticular cells; ECM, extracellular matrix; Nes, nestin; NG2, neuron/glial antigen 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.