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Tosato et al. J Cancer Metastasis Treat 2021;7:52  https://dx.doi.org/10.20517/2394-4722.2021.120  Page 9 of 14

               effective at reducing transfusion requirements in MDS with del(5q), has immunomodulatory and anti-
                                 [92]
               angiogenic functions . Azacytidine and decitabine, pyrimidine nucleoside analogs that inhibit DNA
               methylation and have direct cytotoxicity for abnormal bone marrow hematopoietic cells, may also target the
               abnormal mesenchymal cells, as indicated by co-culture of normal HSC with MDS-derived mesenchymal
               cells with azacytidine . Luspatercept, FDA approved for the treatment of anemia associated with MDS
                                 [66]
               with ring sideroblasts with or without thrombocytosis, traps ligands in the TGF-β superfamily and promotes
               erythroid differentiation. TGF-β is a bone marrow niche factor produced by many cell types in an inactive
               form and is then activated in the bone marrow by non-myelinating Schwann cells that coat sympathetic
               nerves . Immunosuppressive therapies with anti-thymocyte globulin and cyclosporine are effective in
                     [28]
               hypoplastic MDS and/or patients with paroxysmal nocturnal hemoglobinuria-positive cells, rather than
               directly affecting the malignant cells.

               Increased appreciation of bone marrow niches and their contributions to the development and progression
               of MDS and AML, has brought into focus the niche as a potential therapeutic target. This could be
               accomplished by blocking interactions between the malignant cells and their niche; targeting the pro-
               oncogenic bone marrow microenvironment; or targeting the neoplastic cells-derived processes that re-
               program the niche(s). One approach has been to remove malignant hematopoietic cells from their
               supportive niche through mobilization of AML cells using the CXCR4 blocker plerixafor (as done to
               mobilize normal stem/progenitor cells for hematopoietic transplantation in conjunction with G-CSF). This
               approach had shown limited benefit in initial trials [93,94] , but more potent CXCR4 inhibitors hold promise for
               treatment of AML . CD44/E-selectin is a cell surface glycoprotein receptor for hyaluronic acid,
                                [95]
               osteopontin, and other ligands involved in adhesion of HSC and leukemic cells. CD44/E-selectin
               antagonists were effective in experimental mouse models of AML and are now tested in initial clinical
               trials . Similarly, studies in vitro showed that VCAM1 (on the stromal cells) interacting with VLA-4 on the
                   [96]
               leukemic cells induced reciprocal activation of the NF-κB pathway, proposed to promote resistance to
               chemotherapy . The blockade of NF-κB activation reduced drug resistance in AML cells . Currently, the
                           [97]
                                                                                           [97]
               VLA4 inhibitor AS101 is being tested in patients with MDS and AML (NCT01010373).
               The role of Notch signaling in AML appears complex. Human AML samples display increased expression of
               Notch receptors, but they are generally inactive or display basal levels of activity. Activation of Notch
               signaling initiated growth arrest and differentiation of AML cells, suggesting a tumor-suppressive function,
               which provides a rationale for using Notch agonists for the treatment of AML . This approach has not
                                                                                   [98]
               been pursued in clinical development. However, Notch-blocking antibodies neutralized the growth-
               promoting effects imparted by bone marrow stromal cells, suggesting an oncogenic role of Notch in
                    [99]
               AML . This approach is currently under evaluation in clinical trials in T-ALL/T-LBL (NCT02518113).
               Another approach is based on transcriptome profiling of patient-derived AML xenografts, which detected
                                                                                   [82]
               abnormal elevations of endothelial NO in the xenografts and patient samples . Experimental evidence
               additionally showed that NO inhibitors improved the effectiveness of chemotherapy, presumably through
               vessel normalization and reduced permeability . Nitric oxide synthase inhibitors are in clinical trials and
                                                       [82]
                                                      [100]
               have been proposed for clinical testing in AML .
               Other approaches have focused on reducing bone marrow vascularity that accompanies AML. Vessel
               density, abnormally high in MDS and AML, is directly correlated with poor patient outcome. After initial
               encouraging results , a randomized phase-2 trial with the VEGF inhibitor, avastin, did not improve the
                                [101]
               therapeutic outcome of patients with AML . A different approach to reducing the bone marrow
                                                       [102]
               vasculature has focused on blocking Tie2/angiopoietin interaction. The Tie2 receptor is generally expressed
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