Bone marrow niches in myeloid and lymphoid malignancies
Rôle des niches de la moelle osseuse dans les tumeurs malignes myéloïdes et lymphoïdes
Françoise Porteu1, Marie-Bérengère Troadec2,3
1 Inserm U1287, institut Gustave Roussy, Villejuif, France ; 2 Univ Brest, Inserm, EFS, UMR 1078, GGB, Brest, France ; 3 CHRU Brest, service de génétique, laboratoire de génétique chromosomique, Brest, France
* Tirés à part : F. Porteu
This session is proposed by the Club Hématopoïèse et Oncogenèse (CHO), a cooperative group from the SFH. Since 1994, the CHO gather scientists and clinicians interested in normal and pathological hematopoiesis and oncogenesis. It organizes a scientific session at the annual congress of the SFH, and the CHO annual meeting. For more information, visit our site www.cho-hemato.fr
Introduction. In the last decades we have expanded our understanding of the bone marrow (BM) environment. These studies have shed light on the key role of the BM niches in regulating normal hematopoiesis throughout life but also in fostering leukemia development and protecting leukemic cells from chemotherapy. Thus the BM niche represents a promising therapeutic target and is an area of intense research. In this session, recent data characterizing the BM niches and the bi-directional dialogue between stromal and hematopoietic cells in normal hematopoiesis, acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) progression will be presented.
The bone marrow niches. Hematopoietic stem cells (HSCs) reside in a unique BM environment called “HSC niche” that functions as the primary site of hematopoiesis. In the last decade, thanks to the development of modern technologies (genetic mouse models, single cell genomic/transcriptomic, imaging...) the composition of this semi-solid environment has been described with unprecedented resolution. At least two anatomically distinct niches have been described in the BM: i) the central niche. This niche is located in the inner BM and occupies 90% of the BM volume. It contains the majority of sinusoids and arterioles as well as most of the HSCs. This niche is responsible for the daily production of blood cells and its activity is suppressed by irradiation or other genotoxic stresses; ii) the endosteal niche. Located in close proximity to the bone surface, this niche represents 10% of the BM volume. It contains all the transition zone vessels and the reserve of quiescent HSCs. Given its relative resistance to genotoxic insults it seems to play an important role in the regeneration of hematopoiesis after stress. In both central and endosteal niches HSCs reside in perivascular niches. Several types of non-hematopoietic cells maintain HSCs and regulate the balance between HSC self-renewal and differentiation. This includes sympathetic nerve fibers, Schwann cells, vascular endothelial cells and different types of mesenchymal stem cells (MSCs can replicate and exhibit a tri-lineage plasticity giving rise to adipocytes, chondroblasts, and osteoblasts). Despite the localization of HSCs in close proximity to the endosteum, the role of osteoblasts remains unclear. Mature hematopoietic cells such as megakaryocytes and macrophages have also been shown to promote retention of HSCs in the niche.
Single-cell transcriptomics, mass-spectrometry and spatial resolution of the BM environment has revealed a dynamic and highly heterogeneous molecular landscape of niche cell populations, identified cell subsets establishing perivascular microniches and other involved in HSC engraftment. These data have also revealed that the BM niches are subjected to high remodeling under stress and with age [1-5].
It was initially postulated that distinct stromal cell populations can secrete lineage instructive signals to control multipotent progenitors differentiation and that HSCs and lymphoid progenitors occupy distinct niches [6, 7]. Recent data showing that peri-sinusoidal cells coexpress HSC and B-cell supporting factors, and that HSCs and pro-B cells can be found together in the same niche, has challenged this concept [8, 9]. A similar niche was found in humans. Different types of HSCs have been described: platelet, lymphoid or myeloid differentiation primed, dormant, quiescent or activated. It is not yet known whether these HSCs reside in a unique multifunctional niche or in spatially distinct niches.
HSC quiescence and maintenance are controlled by bone marrow non-hematopoietic cells and hematopoietic cells thanks to soluble factors and/or direct interactions [10, 11]. Bone marrow MSCs, namely the CXCL12-abundant reticular cells, express HSC maintenance genes like C-X-C motif chemokine 12 (CXCL12), stem cell factor (SCF), Angiopoietin 1, interleukin 7, VCAM-1 and osteopontin. CXCL12 is also produced by osteoblasts and other cells. CXCL12 interacts with its receptor CXCR4 expressed by HSCs. Bone marrow stromal cells produce osteopontin, also secreted by osteoblasts, and bind to integrins on the surface of HSCs. Thrombopoietin is produced by bone marrow stromal cells and interacts with its receptor, myeloproliferative leukemia virus proto-oncogene (MPL). Sympathetic nerves secrete neuropeptide Y and drive HSC quiescence. Non-myelinated Schwann cells activate TGF-β signaling and CXCL12 expression and also mediate HSC quiescence. Adipocytes drive HSC proliferation. Extracellular matrix is also an important player for HSC survival and maintenance. Finally, mature immune/hematopoietic cells like T- and B-cells, macrophages, or dendritic cells are present in the BM. Megakaryocytes and macrophages induce quiescence by producing TGFβ-1 and prostaglandin E2, respectively. Megakaryocytes can be found in tight contact with HSCs. An important role of these immune cells is to eliminate abnormal cells.
The bone marrow niche in malignancies. The HSC niche is frequently impaired in hematological malignancies. It is also altered by radiotherapy or chemotherapy. This results in defective hematopoiesis and likely contributes to the development of leukemia or in its progression. The BM niche is now increasingly recognized as having an important role in survival and expansion of leukemic stem cells (LSCs). LSCs share many features with healthy HSCs. This includes their dependence from the BM niche for their survival. The niches are also involved in the regulation of angiogenesis, inflammation, and changes associated with increased hypoxia to favor malignant hematopoietic cell maintenance. Finally they facilitate immune evasion, defense against reactive oxygen species, protecting LSCs from chemotherapy, and ultimately causing relapse [9, 11]. Thus the BM niche represents an important therapeutic target to improve treatment outcome.
The importance of the niche in the development or progression of malignancy has been suggested more than two decades ago . Two non-mutually exclusive hypothesis have been proposed to explain this role: i) by acquiring mutations niche cells act as initiating events driving or predisposing to the development of hematopoietic malignancy; ii) the leukemic cells might remodel the niche to create an environment facilitating their expansion and survival. The formal demonstration of the first hypothesis was obtained from murine models. Notably the group of D. Scadden showed that mutation of Dicer in mouse osteoprogenitors was sufficient to alter the differentiation, survival and proliferation of HSCs and progenitors, disrupt tissue homeostasis, resulting in secondary myelodysplasia and leukemia . Several studies have also reported niche-initiating events, with potential oncogenic roles in myeloid malignancies. This includes the development of myeloproliferative neoplasms in mice lacking the NF-κB inhibitor , the retinoic acid receptor  or the tumor suppressor Rb1 in non-hematopoietic cells . However, the relevance of these observations for human pathologies has still to be established. Genetic alterations different from alterations present in the leukemic cells have been reported in MSCs from patients with MDS and AML  but their role in the disease establishment and progression is not yet known.
One common mechanism that could explain aggravation or development of myeloid malignancies by the BM environment is inflammation. Myeloid malignancies are more prevalent in the elderly. Inflammation is a hallmark of normal aging. The aged inflamed BM environment has been shown to promote myeloid cell expansion in various mouse models . Inflammation also favor clonal expansion of HSCs harboring TET2 and DNMT3A mutations which increase with age, and may therefore predispose to the development of myeloid malignancies as we age [19-21]. Other pathways also participate to this myeloid expansion. For example, the loss of the Notch ligand DLL4 expressed by vascular–endothelial cells transcriptionally reprograms HSPCs and skews their differentiation towards myeloid production .
On the other hand, it is now clear that leukemic cells can remodel the BM environment to promote their own proliferation and/or survival, which attests to the existence of an active bidirectional dialogue between the two compartments. Malignant cells reprogram several types of niche cells including osteoblasts, MSCs, adipocytes and endothelial cells and peripheral neurons. Changes in epigenetics, transcriptome, proteome, cytokine or extra-vesicle production, phenotype, number, have been reported in human healthy MSCs after co-culture with MDS or AML malignant cells (reviewed in ). Conversely, MSCs from MDS patients can impair the growth and the differentiation of heathy HSCs. How leukemia cells change their niches is the subject of intense investigation. Again, inflammation plays an important role in this remodeling. Notably, mutated malignant myeloid cells can overproduce proinflammatory cytokines such as IL-6 and IL-1β, and secrete proangiogenic factors such as VEGFA, which in turn promote niche vascularization and cause progressive changes in the BM niche cells, damage MSCs, neurons and their associated Schwann cells . They can also instruct MSCs to provide other survival signals. Acting together these factors will lead to a feedback loop fostering the growth and survival of malignant hematopoietic cells at the expense of healthy cells. Niche remodeling favors malignancy and contribute to their chemoresistance by activating anti-apoptotic pathways, protecting them from oxidative stress and reprogramming their metabolism. Increased and impaired neo-vessel function due to changes in endothelial cells and increase in NO production caused by the leukemic cells in AML and MPN play an important role to compromise the efficiency of chemotherapy. Stromal cells also affect the efficacy of chemotherapy by providing leukemic cells with ROS detoxification mechanisms, such as GSH availability.
Dysfunctions of mature immune cells like T- and B-cells, macrophages, or dendritic cells are also implicated in leukemogenesis. AML develops after immune escape from innate and adaptive immune responses. In particular, the niche can promote an immunosuppressive environment by secreting immunosuppressive factors inhibiting the activation of natural-killer and T-cells, or by recruiting myeloid-derived suppressor cells (MDSCs) . In MDS/MPN with dysplastic myeloid cell expansion, as in CMML, these MDSCs may be part of the malignant clone itself, creating a deleterious feed-forward loop [22, 23].
Disruption of adhesion molecules involved in interactions between different cell types within the BM participates to leukemogenesis. In particular, several adhesion molecules (e.g. E-selectin, CD44, and very late antigen 4 (VLA-4)) were found to play a relevant role in AML. E-selectin is expressed by endothelial cells and interacts with CD44, a cell surface protein detected on a large range of AML samples. VLA-4 is the ligand of VCAM-1, a cell surface protein presented on MSCs. The interaction of VLA-4 and VCAM-1 regulates the NF-κB pathway in both the leukemia and stromal cells, leading to activation of prosurvival and proproliferative pathways and increased resistance to chemotherapy.
The bone marrow niche as a therapeutic target. Targeting the bone marrow niche is viewed as an attractive strategy for improving the outcome of treatment of hematological malignancies in a non-cell autonomous manner. The general strategy is to address specific alterations within the malignant and the supporting niche cells and to inhibit their interaction. Many approaches have been proven to be pertinent and others are under investigation .
A first strategy is to consider cytokines/chemokines receptors as druggable targets for therapeutic options. CXCL12 is expressed by MSCs and regulates the mobilization of HSCs and transformed cells via binding to CXCR4. Disruption of the CXCL12/ CXCR4 interaction by CXCR4 inhibitors represents a novel and promising strategy for the therapy of AML by targeting the BM microenvironment. Indeed, in AML cells, the chemotherapy stress induces the expression of CXCR4 and leads to increased resistance and survival. Inhibition of CXCR4 sensitizes AML to chemotherapy and increased therapy-induced apoptosis. Blocking the CXCL12/CXCR4 interaction also helps to release AML and MPN cells from their protective niches to make them available for chemotherapy . Different types of small antagonists, including small molecules such as AMD3100 and monoclonal antibodies are already under clinical investigation. In addition, targeting inflammatory cytokines is also promising in MDS. Indeed, in MDS patients, MSCs, stromal fibroblasts and macrophages expression profiles revealed upregulation of pro-inflammatory cytokines linked to inhibition of hematopoiesis, like TNF-α, interleukin-6, interferon γ or TGF-β. The TGF-β superfamily can be blocked therapeutically (luspatercept), restoring late-stage erythropoiesis .
A second strategy is to target adhesion proteins and alter the direct interaction between the leukemic cells and the niche cells. In AML, blocking E-selectin under chemotherapy increases apoptosis rate of AML. Clinical trials to test the capacity of E-selectin antagonists are in progress. Similarly, interaction between VLA-4 expressed by hematopoietic cells and VCAM-1 on MSCs and can be targeted by a small molecule inhibitor AS101. A pre-clinical phase of drug development is under investigation in AML.
A third strategy is related to antiangiogenic therapy. Increased vascularization of the bone marrow under the control of VEGF is observed in MDS, MPN, and AML. Antiangiogenic therapies are targeting the binding of VEGF to VEGFR either by small molecules (tyrosine kinase inhibitors), anti-VEGF monoclonal antibodies or immunomodulatory drugs like lenalidomide.
A fourth approach is to use immunotherapy. Immune evasion is challenging to eliminate leukemia-initiating clones. The goal is to activate the adaptive immune system and overcome the immunosuppressive properties of transformed cells (reviewed in ). Many strategies are developed. They include blocking antibodies for immune checkpoint proteins (like PD-1), bispecific T-cell engager (BiTE) and Dual-Affinity Re-Targeting (DART) diabody (they connect T-cells via the CD3 surface receptor to tumor cells leading to their lysis.) The combination of immune checkpoint blockade therapy with the hypomethylating agent azacytidine has shown remarkable clinical efficacy in AML . Immunotherapy approach also consists of autologous/allogeneic T-cells engineered with synthetic chimeric antigen receptors (CARs), or more recently “armored” CAR–T cells capable of manipulating the tumor microenvironment to favor cell death. A final approach consists in promoting phagocytosis of leukemia-initiating AML cells or ALL (reviewed in ) by targeting the CD47/SIRP-α pathway which is an essential immune checkpoint protein for the regulation of innate immune cells. CD47 is expressed at the surface of AML cells whereas SIRP-α is expressed on monocytes and macrophages. CD47-inhibiting monoclonal antibody approaches have been developed.
A fifth approach is to modulate the metabolism of cancer cells. For instance, hypoxia-activated prodrugs might have clinical implications.
Finally, the sixth approach, which is not exclusive from the previous ones, is to consider targeting extra medullary leukemia. Some extra medullary niches share common players with bone marrow niche, including CXCL12/CXCR4 axis or low oxygen concentrations (reviewed in ). Extramedullary AML occurs in 10–40% of pediatric AML and is observed in skin, muscle, bone, gingival tissue, and brain. CXCL12/CXCR4 and CXCL12/CXCR7 interactions facilitate the retention of AML cells and prolong AML cell survival, respectively .
During this session the contributions of the BM niche to these cross-talks and niche alterations in AML will be further developed by Diana Passaro from Cochin institute who is investigating the changes occurring in the vascular niche and BM mesenchymal cells during the development of AML, using a combination of OMICs and imaging in patient's xenografts, as well as genetic and tissue engineering tools. Raphael Argüello (CIML, Marseille) will present SCENITH a powerful technology allowing to profile energetic metabolism at the single cell level combined with global levels of epigenetic markers that could serve as a tool to identify the pathways involved in AML chemoresistance and the remodeling of the various stromal and immune cells in the niche. Stéphane Mancini (MICMAC, INSERM U1236, Rennes) will introduce B cell niches and challenge the concept of the heterogeneity of mesenchymal stromal cell defining HSC- or lineage-specific niches by showing that hematopoietic niches in the BM can be multifunctional. He will also discuss the role of newly identified niche factors sustaining B cell development in B-ALL growth.
Conflicts of interest. The authors declare that they have no links of interest in relation to this article.
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Unravel the role of the vascular niche in the leukemic microenvironment
Cochin Institute, Paris, France
Acute leukemias are aggressive cancers developing both during childhood and adult life, with poor overall prognosis. The main intervention line is high-dose chemotherapy, often associated with resistance, relapse and long-term side effects. Although predominantly considered as genetic diseases, acute leukemias also affect the function of their microenvironment, and vice versa, pointing towards the existence of an active crosstalk between the two compartments.
The use of genetic mouse models associated with powerful imaging and sequencing techniques have allowed the characterization of the bone marrow (BM) tissue at unprecedent resolution. We have highlighted specific transcriptomic changes in the BM microenvironment occurring during the development of different acute leukemias. By using a proximity based molecular approach, we have identified early disease onset deregulated genes in the BM mesenchymal niche. The integration of the BM transcriptome and secretome allowed the prediction of signaling nodes involved in niche alteration in acute myeloid leukemia (AML).Among the others, the vascular niche stands as an essential component of the leukemic microenvironment, with a peculiar implication in both myeloid and lymphoid leukemias. We have previously shown that AML progression and drug resistance are influenced by the interaction with an altered vascular niche in the BM. The detection of vascular aberrations in patients would be of high clinical value as biomarkers helping to predict the clinical outcome and direct the appropriate treatment. We have recently implemented diagnostic imaging protocols allowing the rapid translation of our observations into clinical settings. We are currently combining imaging with genetic and tissue engineering tools to visualize, understand and manipulate the vascular niche at multiple tissue level with the aim of unraveling its complex function in leukemia disease progression, dissemination and drug resistance
Conflicts of interest. The author declares that he has no links of interest in relation to this article.
Epigenetic and Metabolic determinants of chemosensitivity using a SCENITH-based approach
Hatem Abou-Guendia, Ania I. Baaziz, Julien P. Gigan, Evelina Gatti*, Philippe Pierre*, Rafael J. Argüello
CIML, Marseille, France
* Equally contributed
Most AML patients do not respond to current chemotherapies and only 15% show a complete response. The lack of predictive markers of treatment efficacy in AML results in treating all patients with chemotherapeutic drugs that have severe side effects and that fail in ≈85% of the cases. A major factor in disease relapse is clonal heterogeneity inherent in individual tumors. It is well-known that minimal residual disease (MRD) after initial leukemia therapy predicts for relapse and poor clinical outcomes, suggesting that pre-existing resistant clones arise from underlying tumor heterogeneity and persist through treatment selection. It has been recently shown, that metabolic parameters of AML blasts correlate with their sensitivity to chemotherapeutic treatments but the underlying mechanisms are unknown. The three most commonly used chemotherapeutic drugs in AML patients target epigenetics (i.e hypomethylating agents AraC and AZA) or mitochondrial anti-apoptotic protein BCL-2 (i.e. Venetoclax). A link between epigenetics and metabolism might underlie the sensitivity or resistance to these molecules. Metabolism not only fuel the energetic demands of cells but also it provides acetyl-CoA, NAD+, α-KG and other substrates and cofactors of the epigenetic machinery. Epigenetic changes regulate gene and transposon expression programs and thus, metabolism may regulate gene expression and function of immune and transformed leukemic cells. There is a lack of methods to determine in parallel metabolism and epigenetics ex-vivo. Here, we use SCENITH, a technology to profile the energetic metabolism with single cell resolution ex-vivo and combined it in one assay to determine global levels of epigenetic markers. We tested the sensitivity to chemotherapy and the links between phenotypic and functional metabolism and levels of histone modifications in different AML lines and recently in patient samples. We were able to identify that mitochondrial mass, but not mitochondrial dependency correlate with the level of epigenetic marks and with chemosensitivity. More importantly, we observed that low mitochondrial dependence by SCENITH and high mitochondrial mass was associated with increased sensitivity to hypomethylating agents and Venetoclax. In conclusion, we identified metabolic markers in AML lines that can potentially predict response of leukemic blasts to current chemotherapies. We envision the use of SCENITH as a personalized medicine tool that can reveal metabolic and epigenetic heterogeneity associated with treatment resistance in patients with AML.
Conflicts of interest. The authors declare that they have no links of interest in relation to this article.
Bone marrow stromal cell niches in the development of normal and pathological B cells
Inserm 1236, Rennes, France
After birth, development of hematopoietic cells occurs in the bone marrow. It is now clear that the bone marrow microenvironment plays an essential role in the maintenance of hematopoietic stem cells (HSC) and differentiation into more mature lineages. Mesenchymal and endothelial cells contribute to a protective microenvironment called hematopoietic niches that secrete specific factors and establish direct contact with developing hematopoietic cells. A number of recent studies have addressed the specific molecular events that are involved in the cellular crosstalk between hematopoietic subsets and their niches. The influence of BM microenvironment on pathologies affecting hematopoietic progenitors has taken benefits from the important advances in normal HSC niche characterization. Resistance and relapse in the case of B cell acute lymphoblastic leukemia (B-ALL), pathological equivalent of differentiating B cells, also concerns a great proportion of patients, most particularly adults. It is now clear that part of the resistance to treatment is related to protective cues transmitted by stromal cells.
Niche heterogeneity is still a matter of debate. In the lab, we observed that the diversity of BM mesenchymal subsets is limited and found that peri-sinusoidal stromal (PSS) cells form a unique subset which has the capacity to sustain both HSC maintenance and early B cell development. Development of an interactome bioinformatics pipeline allowed the identification of ligand/receptor pairs involved in LT-HSC or pro-B cell specific interaction with PSS cells. As expected, we recovered genes known to be implicated in HSC maintenance and lymphoid development respectively, but we also identified a new ligand/receptor pair involved in pro-B cell retention in the niche. We finally extended our knowledge about normal BM niches to pathology and found that factors expressed by normal stromal cell niches can play a crucial role in B-ALL growth. These results pave the way towards the generation of new adjuvant therapeutic strategies targeting the interactions between leukemic cells and their microenvironment in order to decrease resistance to chemotherapy.
Conflicts of interest. The author declares that he has no links of interest in relation to this article.