The bone-marrow niche in MDS and MGUS: implications for AML and MM

Key Points Multiple myeloma is almost always preceded by monoclonal gammopathy of undetermined significance, and at least one-quarter of all patients with myelodysplastic syndromes (MDS) have disease that evolves into acute myeloid leukaemia; in turn, MDS are frequently anteceded by clonal haematopoiesis of indeterminate potential The bone-marrow microenvironment has been recognized to be a vibrant and complex living tissue that can aid and abet neoplastic disease processes Neoplastic clones can transform the local bone-marrow microenvironment to favour their own growth at the expense of nonmalignant haematopoietic cells An intricate and dynamic relationship between stem cell 'seeds' and the niche 'soil' helps to determine whether healthy haematopoiesis or an overgrowth of haematological malignancies occurs within the bone marrow Targeting microenvironment-specific alterations might not only prevent disease progression from precursor states but also enhance the effectiveness of available therapies for the overt malignancies once progression has occurred Both multiple myeloma and acute myeloid leukaemia are often preceded by defined precursor stages of neoplasia, which can aid efforts to unravel the mechanisms of disease progression. Herein, the authors review studies of the important roles of microenvironmental factors in promoting the development and progression of haematological cancers in these precursor conditions. Potential therapeutic strategies targeting the abnormal bone-marrow microenvironment are discussed. Several haematological malignancies, including multiple myeloma (MM) and acute myeloid leukaemia (AML), have well-defined precursor states that precede the development of overt cancer. MM is almost always preceded by monoclonal gammopathy of undetermined significance (MGUS), and at least a quarter of all patients with myelodysplastic syndromes (MDS) have disease that evolves into AML. In turn, MDS are frequently anteceded by clonal haematopoiesis of indeterminate potential (CHIP). The acquisition of additional genetic and epigenetic alterations over time clearly influences the increasingly unstable and aggressive behaviour of neoplastic haematopoietic clones; however, perturbations in the bone-marrow microenvironment are increasingly recognized to have key roles in initiating and supporting oncogenesis. In this Review, we focus on the concept that the haematopoietic neoplasia–microenvironment relationship is an intimate rapport between two par