Advances in understanding the acute lymphoblastic leukemia bone marrow microenvironment: From biology to therapeutic targeting.
The bone marrow (BM) microenvironment regulates the properties of healthy hematopoietic stem cells (HSCs) localized in specific niches. Two distinct microenvironmental niches have been identified in the BM, the "osteoblastic (endosteal)" and "vascular" niches. Nevertheless, these niches provide sanctuaries where subsets of leukemic cells escape chemotherapy-induced death and acquire a drug-resistant phenotype. Moreover, it is emerging that leukemia cells are able to remodel the BM niches into malignant niches which better support neoplastic cell survival and proliferation. This review focuses on the cellular and molecular biology of microenvironment/leukemia interactions in acute lymphoblastic leukemia (ALL) of both B- and T-cell lineage. We shall also highlight the emerging role of exosomes/microvesicles as efficient messengers for cell-to-cell communication in leukemia settings. Studies on the interactions between the BM microenvironment and ALL cells have led to the discovery of potential therapeutic targets which include cytokines/chemokines and their receptors, adhesion molecules, signal transduction pathways, and hypoxia-related proteins. The complex interplays between leukemic cells and BM microenvironment components provide a rationale for innovative, molecularly targeted therapies, designed to improve ALL patient outcome. A better understanding of the contribution of the BM microenvironment to the process of leukemogenesis and leukemia persistence after initial remission, may provide new targets that will allow destruction of leukemia cells without adversely affecting healthy HSCs. This article is part of a Special Issue entitled: Tumor Microenvironment Regulation of Cancer Cell Survival, Metastasis,Inflammation, and Immune Surveillance edited by Peter Ruvolo and Gregg L. Semenza.
Institute of Molecular Genetics, National Research Council, Rizzoli Orthopedic Institute, Bologna, Italy.
Francesca
F
Chiarini
Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.
Annalisa
A
Lonetti
Institute of Molecular Genetics, National Research Council, Rizzoli Orthopedic Institute, Bologna, Italy.
Camilla
C
Evangelisti
Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
Francesca
F
Buontempo
Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
Ester
E
Orsini
Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
Cecilia
C
Evangelisti
Department of Human Social and Health Sciences, University of Cassino, Cassino, Italy.
Alessandra
A
Cappellini
Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy.
Luca M
LM
Neri
Department of Microbiology & Immunology, Brody School of Medicine, East Carolina University, Greenville, NC, USA.
James A
JA
McCubrey
Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy. Electronic address: alberto.martelli@unibo.it.
Alberto M
AM
Martelli
D000970:Antineoplastic Agents / Q000627:therapeutic use; D001853:Bone Marrow / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D015815:Cell Adhesion Molecules / Q000378:metabolism; D018925:Chemokines / Q000378:metabolism; D006801:Humans; D008954:Models, Biological; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D015398:Signal Transduction / Q000187:drug effects; D055153:Stem Cell Niche; D059016:Tumor Microenvironment
D000970:Antineoplastic Agents; D015815:Cell Adhesion Molecules; D018925:Chemokines
Chemoresistance; Exosomes/microvesicles; Hypoxia; Leukemia initiating cells; Relapse; Signaling pathways