Mesenchymal stromal cell senescence in haematological malignancies

Abstract

Acute myeloid leukaemia (AML), chronic lymphocytic leukaemia (CLL), and multiple myeloma (MM) are age-related haematological malignancies with defned precursor states termed myelodysplastic syndrome (MDS), monoclonal B-cell lymphocytosis (MBL), and monoclonal gammopathy of undetermined signifcance (MGUS), respectively. While the progression from asymptomatic precursor states to malignancy is widely considered to be mediated by the accumulation of genetic mutations in neoplastic haematopoietic cell clones, recent studies suggest that intrinsic genetic changes, alone, may be insuffcient to drive the progression to overt malignancy. Notably, studies suggest that extrinsic, microenvironmental changes in the bone marrow (BM) may also promote the transition from these precursor states to active disease. There is now enhanced focus on extrinsic, age-related changes in the BM microenvironment that accompany the development of AML, CLL, and MM. One of the most prominent changes associated with ageing is the accumulation of senescent mesenchymal stromal cells within tissues and organs. In comparison with proliferating cells, senescent cells display an altered profle of secreted factors (secretome), termed the senescence-associated-secretory phenotype (SASP), comprising proteases, infammatory cytokines, and growth factors that may render the local microenvironment favourable for cancer growth. It is well established that BM mesenchymal stromal cells (BM-MSCs) are key regulators of haematopoietic stem cell maintenance and fate determination. Moreover, there is emerging evidence that BM-MSC senescence may contribute to age-related haematopoietic decline and cancer development. This review explores the association between BM-MSC senescence and the development of haematological malignancies, and the functional role of senescent BM-MSCs in the development of these cancers.