Location First: Targeting Acute Myeloid Leukemia Within Its Niche

Abstract

Despite extensive research and development of new treatments, acute myeloid leukemia (AML)-backbone therapy has remained essentially unchanged over the last decades and is frequently associated with poor outcomes. Eradicating the leukemic stem cells (LSCs) is the ultimate challenge in the treatment of AML. Emerging evidence suggests that AML remodels the bone marrow (BM) niche into a leukemia-permissive microenvironment while suppressing normal hematopoiesis. The mechanism of stromal-mediated protection of leukemic cells in the BM is complex and involves many adhesion molecules, chemokines, and cytokines. Targeting these factors may represent a valuable approach to complement existing therapies and overcome microenvironment-mediated drug resistance. Some strategies for dislodging LSCs and leukemic blasts from their protective niche have already been tested in patients and are in different phases of the process of clinical development. Other strategies, such as targeting the stromal cells remodeling processes, remain at pre-clinical stages. Development of humanized xenograft mouse models, which overcome the mismatch between human leukemia cells and the mouse BM niche, is required to generate physiologically relevant, patient-specific human niches in mice that can be used to unravel the role of human AML microenvironment and to carry out preclinical studies for the development of new targeted therapies.

Keywords: acute myeloid leukemia (AML); bone marrow niche; bone marrow stromal cells; leukemic stem cell (LSC); targeted therapy.

Figure 1

Acute myeloid leukemia (AML) cells interactions with the bone marrow (BM) niche. The BM microenvironment is composed of multiple different cell populations (mesenchymal stromal cells, adventitial reticular cells, sinusoidal endothelial cells, osteoblasts) and non-living extracellular matrix (osteopontin, fibronectin, hyaluronan). All these factors facilitate adhesion of LSCs and AML cells to the BM niche and regulate the migration, homing, survival, proliferation and chemotherapeutic agents’ resistance of AML cells. The following interactions have been reported to be involved: VLA-4/VCAM-1, VLA-4/FN, CD98/integrins, CD44/OPN, CD44/HA, ESL-1/E-selectin. All of them are under clinical investigation for therapies which may specifically disrupt the crosstalk of LSCs with the BM niche. The most relevant therapeutic molecules are outlined (red). MSC: mesenchymal stromal cell; LSC: leukemic stem cell; OPN: osteopontin; FN: fibronectin; HA: hyaluronan; VLA-4: very late antigen-4; VCAM-1: vascular cell adhesion molecule-1; ESL-1: E-selectin ligand-1. This figure has been created with Biorender.com.

Figure 2

Soluble mediators involved in AML-BM niche crosstalk. (A) Chemokines contribute to cell proliferation, survival and chemotaxis. All these functions are important for the development of the AML-supportive BM niche. The chemokine axes involved in AML are the well-known CXCL12/CXCR4 axis and the newly investigated CCL2/CCR2 and CXCL8/CXCR1-CXCR2 axes. The most significant therapeutic agents and the pre-clinical molecules are outlined (red). At present, Plerixafor combined with conventional chemotherapy is under clinical investigation, whereas the other drugs represented refer to potential therapeutic approaches that still need to be evaluated in clinical trials. (B) In addition to chemokines, other subfamilies of cytokines are also dysregulated in the BM microenvironment. The pro-inflammatory mediators, such as interleukin (IL)-1, IL-6 and tumor necrosis factor (TNF)-α provide support to AML progression, while the immunosuppressive factors, like TGF-β and IL-10, can be downregulated/mutated and contribute to leukemia immune escape, respectively. Due to the pleiotropic nature of cytokines and the lack of detailed knowledge on the specific molecular players involved in their downstream signaling pathways, few clinical trials are investigating new drugs in the context of AML. The most promising are: Ruxolitinib, inhibiting IL-6/IL-6R interaction, that is being clinically evaluated in combination with decitabine in AML patients; Anakinra, Rilanocept and Canakinumab, which are FDA approved therapeutic agents indicated for inflammatory diseases, that still need to be tested in pre-clinical AML models. MSC: mesenchymal stromal cell; LSC: leukemic stem cell; CCL2: C-C motif chemokine ligand-2; CCR2: C-C motif chemokine receptor 2; CXCR1: C-X-C motif chemokine receptor 1; CXCR2: C-X-C motif chemokine receptor 2; CXCR4: C-X-C motif chemokine receptor 4; CXCL8: C-X-C motif chemokine ligand 8; CXCL12: C-X-C motif chemokine ligand 12; TNF- α: tumor necrosis factor alpha; TNF-R: tumor necrosis factor receptor; TGF-β: transforming growth factor beta; IFN-γ: interferon gamma; IFN-R: interferon receptor; IL-1: interleukin-1; IL-1R: interleukin-1 receptor. This figure has been created with Biorender.com.

Figure 3

Osteogenic niche in leukemogenesis. (A) Leukemic cells reprogram BM niche into a self-reinforcing leukemic microenvironment. AML blasts induce osteogenic differentiation in MSCs through cell-to-cell contact and secretion of chemokine ligand 3 (CCL3) and bone morphogenetic proteins (BMP). Reduction of the sympathetic nervous system promotes the expansion of osteoblastic-primed MSCs, which can contribute to AML progression. Exosomes containing microRNAs (miRNAs) are secreted and uptaken by MSCs, impairing HSC function and favoring the proliferation of dysplastic cells. (B) Mutations in niche components have been associated with the initiation of myeloid malignancies. An activating mutation of β-catenin in osteoblasts induces AML in mice through upregulation of Jagged-1 expression. As a result, Notch1 signaling is activated in HSCs. A mutation in Dicer1 in Osterix+-osteoprogenitors deregulates HSCs that become dysplastic and eventually transform to AML. An activating mutation of the protein tyrosine phosphatase SHP2 (encoded by Ptpn11) in Nestin (Nes)⁺ MSCs leads to increased risk of leukemic transformation of HSCs via overproduction of CCL3. Potential therapeutic approaches targeting the MSCs remodeling and mutations are at pre-clinical stages (red). HSC: hematopoietic stem cell; LSC: leukemic stem cell; MSC: mesenchymal stromal cell; BMP: bone morphogenetic proteins; CCL3: C-C motif chemokine ligand 3; SNS: sympathetic nervous system; β2-AR: β2-adrenergic receptors; MDS: myelodysplastic syndrome; JAG1: Jagged1; ATRA: all-trans-retinoic acid. This figure has been created with Biorender.com.