Mesenchymal Stromal Cells (MSCs): An Ally of B-Cell Acute Lymphoblastic Leukemia (B-ALL) Cells in Disease Maintenance and Progression within the Bone Marrow Hematopoietic Niche
Abstract
:Simple Summary
Abstract
1. Introduction
1.1. Mesenchymal Stromal Cells (MSCs) as Key Regulators of the Healthy Hematopoietic Bone Marrow Niche
1.1.1. MSCs: Main Characteristics
1.1.2. Role of MSCs in the Endosteal and Perivascular BM Niches
1.1.3. Role of Adipocytes in the Healthy Hematopoietic BM Niche
1.2. Acute Lymphoblastic Leukemia (ALL): A Genetic Disease with a Crucial BM Niche Contribution
2. MSCs as Key Modulators of Leukemia Onset, Maintenance, Progression and Drug Resistance within the B-ALL BM Niche
2.1. MSCs Contribute to B-ALL Pathogenesis and Progression by Creating a Leukemia-Supportive BM Microenvironment Rich of Transforming Growth Factor β (TGF β) Family Molecules and Inflammatory Mediators
2.1.1. MSCs Contribute to the Alteration of TGFβ Family Members, Implicated in B-ALL Onset and Progression
2.1.2. MSCs Contribute to the Creation of a Highly Pro-Inflammatory and Pro-Leukemic Cytokine Milieu within the B-ALL BM Niche
2.2. MSCs/Leukemia Crosstalk Is Essential for the Creation of Altered Pro-Leukemic Chemokine Axes within the B-ALL BM Niche
2.2.1. CXCL12/CXCR4 Axis
2.2.2. Other Chemokine Axes Involved in B-ALL Pathogenesis
2.3. MSCs Exchange Amino Acids, Metabolites and Mitochondria with B-ALL Cells to Promote Chemoresistance and Provide an Antioxidant Defense
2.3.1. MSCs Protect B-ALL Cells from Chemotherapy-Based Amino Acid Depletion by Providing Ready-to-Use Amino Acids
2.3.2. MSCs Protect B-ALL Cells from Chemotherapy by Means of a Tunneling Nanotubes-Based Transfer of Mitochondria and Other Cellular Components
2.3.3. B-ALL Cells Secrete Large Amounts of EVs to Reprogram MSCs and Modify the Behavior of Surrounding Cells
2.4. MSC/Leukemic Cell Adhesion Activates Molecular Pathways Promoting B-ALL Maintenance, Chemoprotection and Progression
2.4.1. MSCs Chemoprotect Adherent B-ALL Blasts through Integrin-Mediated Mechanisms
2.4.2. MSCs Chemoprotect B-ALL Blasts through the Exosomal Release of the Adhesion Protein Galectin-3
2.5. MSC/Leukemic Cell Crosstalk Instructs MSCs to Secrete Altered Matricellular Proteins to Create a Leukemia-Favoring ECM
2.6. MSCs Shape the Immune Microenvironment of the B-ALL BM Niche
3. Conclusions and Future Perspective
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Target | Compound | Mechanism of Action | Phase of Study/ Disease Approval | Clinical Trial Number 1 |
---|---|---|---|---|
Asparagine | ASNase | Asparagine depletion | Approved by regulatory agencies for ALL treatment and non-Hodgkin’s lymphoma. In clinical trials for T-ALL, AML, MDS, etc. | NCT00501826, NCT00369317 |
Arginine | BCT-100 | Arginase depletion | Clinical Trial for r/r ALL, r/r AML, hepatocellular carcinoma, melanoma and prostate adenocarcinoma | NCT03455140, NCT02089763, NCT02285101 |
TNTs | Vincristine | Disruption of actin cytoskeleton (TNTs disassembly) | Approved by regulatory agencies for B-ALL treatment and in clinical trials for advanced follicular lymphoma, non-Hodgkin’s lymphoma, Mantle Cell Lymphoma etc. | NCT03817853, NCT00911183, NCT05051891 |
CXCR4/CXCL12 axis | Plerixafor | CXCR4 inhibitor | Clinical Trial for r/r B-ALL, AML and MM. | NCT01319864, NCT02605460, NCT00903968 |
CXCR4/CXCL12 axis | BTK140 | CXCR4 inhibitor | Clinical trial for T-ALL/lymphoma and r/r AML. | NCT02763384, NCT01838395 |
CCR4/CCL22 axis | Mogamulizumab [55] | CCL22/CCR4 inhibitor | Approved by regulatory agencies for r/r mycosis fungoides and Sézary syndrome. Clinical trials for peripheral and cutaneous T-cell lymphoma and adult T-cell leukemia/lymphoma and advanced/metastatic solid tumors. | NCT04745234, NCT00888927, NCT04848064, NCT01929486 |
PKC isoforms | HKPS | Chimeric peptide | Pre-clinical research. | N.A |
ITGA4 | Natalizumab | Monoclonal antibody | Approved by regulatory agencies for multiple sclerosis and Crohn’s disease. Clinical trial for osteosarcoma and multiple myeloma, and pre-clinical evaluation for B-ALL. | NCT03811886, NCT00675428 |
Proteasome inhibitor | Bortezomib | Interference with B-ALL/MSCs interaction | Approved by regulatory agencies for MMtreatment and in Clinical Trials for leukemias and diffuse large B cell lymphoma. | NCT03811886, NCT00675428 |
TGFBR1 inhibitor | Vactosertib | Inhibits the intracellular signaling of TGFβ | Clinical trial for colorectal cancer and blood cancers. | NCT05400122 |
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Fallati, A.; Di Marzo, N.; D’Amico, G.; Dander, E. Mesenchymal Stromal Cells (MSCs): An Ally of B-Cell Acute Lymphoblastic Leukemia (B-ALL) Cells in Disease Maintenance and Progression within the Bone Marrow Hematopoietic Niche. Cancers 2022, 14, 3303. https://doi.org/10.3390/cancers14143303
Fallati A, Di Marzo N, D’Amico G, Dander E. Mesenchymal Stromal Cells (MSCs): An Ally of B-Cell Acute Lymphoblastic Leukemia (B-ALL) Cells in Disease Maintenance and Progression within the Bone Marrow Hematopoietic Niche. Cancers. 2022; 14(14):3303. https://doi.org/10.3390/cancers14143303
Chicago/Turabian StyleFallati, Alessandra, Noemi Di Marzo, Giovanna D’Amico, and Erica Dander. 2022. "Mesenchymal Stromal Cells (MSCs): An Ally of B-Cell Acute Lymphoblastic Leukemia (B-ALL) Cells in Disease Maintenance and Progression within the Bone Marrow Hematopoietic Niche" Cancers 14, no. 14: 3303. https://doi.org/10.3390/cancers14143303