Bone marrow niches in haematological malignancies

Abstract

Haematological malignancies were previously thought to be driven solely by genetic or epigenetic lesions within haematopoietic cells. However, the niches that maintain and regulate daily production of blood and immune cells are now increasingly being recognized as having an important role in the pathogenesis and chemoresistance of haematological malignancies. Within haematopoietic cells, the accumulation of a small number of recurrent mutations initiates malignancy. Concomitantly, specific alterations of the niches, which support haematopoietic stem cells and their progeny, can act as predisposition events, facilitating mutant haematopoietic cell survival and expansion as well as contributing to malignancy progression and providing protection of malignant cells from chemotherapy, ultimately leading to relapse. In this Perspective, we summarize our current understanding of the composition and function of the specialized haematopoietic niches of the bone marrow during health and disease. We discuss disease mechanisms (rather than malignancy subtypes) to provide a comprehensive description of key niche-associated pathways that are shared across multiple haematological malignancies. These mechanisms include primary driver mutations in bone marrow niche cells, changes associated with increased hypoxia, angiogenesis and inflammation as well as metabolic reprogramming by stromal niche cells. Consequently, remodelling of bone marrow niches can facilitate immune evasion and activation of survival pathways favouring malignant haematopoietic cell maintenance, defence against excessive reactive oxygen species and protection from chemotherapy. Lastly, we suggest guidelines for the handling and biobanking of patient samples and analysis of the niche to ensure that basic research identifying therapeutic targets can be more efficiently translated to the clinic. The hope is that integrating knowledge of how bone marrow niches contribute to haematological disease predisposition, initiation, progression and response to therapy into future clinical practice will likely improve the treatment of these disorders.

Figures

Fig. 1:. Main features of anatomically-defined haematopoietic stem cell niches in the mouse bone marrow.

Schematic summarizing the key cell types and functional features of the central and endosteal bone marrow (BM) niches of haematopoietic stem cells (HSCs). Mesenchymal stem cells (MSCs; also known as mesenchymal stem and progenitor cells) give rise to bone-forming cells (osteoblasts) and fat cells (adipocytes), whereas bone-resorbing cells (osteoclasts) share a monocytic origin with macrophages. Nestin-GFPhi neural–glial antigen 2 (NG2)+ MSCs are associated with endosteal transition zone vessels and arterioles located throughout the BM, whereas Nestin-GFPlo leptin receptor (LEPR)+ CXC-chemokine ligand 12 (CXCL12)-abundant reticular (CAR) MSCs are associated with sinusoids in the central BM. Sympathetic nerve fibres regulate the migration of HSCs through the sinusoids. Different MSC subpopulations, endothelial cells, non-myelinating Schwann cells and megakaryocytes might contribute to regulate the balance between HSC proliferation and quiescence during daily or regenerative haematopoiesis. Changes in specialized BM niches might directly affect myeloid versus lymphoid output, and the imbalanced production of mature haematopoietic cells at specific niches might, in turn, remodel the local microenvironment for these cells. During ageing, the landscape of the mouse HSC niche changes substantially. Specifically, the central niche expands with morphological and functional changes including an increase in noradrenergic fibres, capillaries with Nestin-GFP+ MSCs, HSC proliferation and myelopoiesis. By contrast, the endosteal niche and its associated components and functions are reduced with concomitant decreases in transition zone vessels and arterioles, HSC quiescence and self-renewal, resistance to genotoxic stress, regenerative haematopoiesis and lymphopoiesis.

Fig. 2:. Bone marrow niche remodelling favours disease progression in haematological malignancies.

Representative features of the remodelled bone marrow (BM) niche contributing to the progression of different haematological malignancies. These diseases can arise through genetic and/or epigenetic alterations in haematopoietic cells causing remodelling of the niche that supports their own growth and survival at the expense of normal haematopoiesis. Myeloproliferative neoplasm (MPN) and acute myeloid leukaemia (AML) cells cause neuroglial damage (affecting Schwann cells and sympathetic nerve fibres) in the BM and reduced expression of CXC-chemokine ligand 12 (CXCL12) in mesenchymal stem cells (MSCs). In MPN, the neuroglial damage is caused by increased production of cytokines, like interleukin-1β (IL-1β), leading to apoptosis of Nestin-GFP+ MSCs, which can be rescued through chronic treatment with sympathicomimetic drugs that indirectly improve reticulin fibrosis in mice and humans. In AML, a reduction in BM sympathetic innervation has been correlated with proliferation of Nestin-GFP+ MSCs primed for osteoblastic differentiation at the expense of neural–glial antigen 2 (NG2)+ periarteriolar niche cells, although the potential relevance of these alterations in human AML is unclear. Increased growth arrest-specific 6 (GAS6) and placental growth factor (PlGF) expression by BM MSCs fosters leukaemia cell survival, proliferation and therapy resistance. Vascular endothelial growth factor (VEGF) secreted by both malignant haematopoietic cells and osteoblasts stimulates angiogenesis. In addition, other factors produced by endothelial cells (such as granulocyte–macrophage colony-stimulating factor (GM-CSF), IL-6 and stem cell factor (SCF)) promote survival and proliferation of malignant haematopoietic cells. IL-6 produced by chronic myeloid leukaemia (CML) cells renders non-mutated haematopoietic and stromal cells pro-inflammatory. Malignant haematopoietic cells stimulate expansion of stromal cells through secretion of growth factors, such as bone morphogenetic proteins (BMPs). A reciprocal relationship occurs between malignant haematopoietic cells and adipocytes wherein malignant cells induce lipolysis from adipocytes and, in turn, adipocytes release fatty acids, which are used as an energy source by malignant haematopoietic cells. Blue arrows in this figure indicate processes or factors secreted by niche cells and black arrows indicate processes or factors released by malignant haematopoietic cells. ALL, acute lymphoblastic leukaemia; CLL, chronic lymphocytic leukaemia; FGF2, fibroblast growth factor 2; MDS, myelodysplastic syndrome; MIP1α, macrophage inhibitory protein 1α; TPO, thrombopoietin.

Fig. 3:. Contributions of the bone marrow niche to survival and chemoresistance of malignant haematopoietic cells.

Schematic showing the diverse mechanisms by which reprogrammed niche cells promote the survival, metabolism and chemoresistance of malignant haematopoietic cells. Different stromal cells in the bone marrow (BM), such as endothelial cells, mesenchymal stem cells (MSCs) and adipocytes, provide metabolic support to malignant haematopoietic cells, which in turn produce angiocrine factors promoting neovascularization in the BM. Induction of protein kinase C-β (PKCβ) in niche cells or B cell-activating factor (BAFF) and a proliferation-inducing ligand (APRIL) signalling from neutrophils can stimulate malignant haematopoietic cell survival. Interleukin-8 (IL-8) and CC-chemokine ligand 2 (CCL2) expression by MSCs recruits and activates neutrophils, which render MSCs pro-inflammatory through nuclear factor-κB (NF-κB) activation, which is also induced in other niche cells and in malignant haematopoietic cells. Cysteine (Cys) secreted by niche stromal cells can be utilized by cancer cells to synthesize glutathione (GSH) and reduce levels of reactive oxygen species (ROS).