title: Bone marrow microenvironment modulation of acute lymphoblastic leukemia phenotype.
abstract: Acute lymphoblastic leukemia (ALL) treatment regimens have dramatically improved the survival of ALL patients. However, chemoresistant minimal residual disease that persists following cessation of therapy contributes to aggressive relapse. The bone marrow microenvironment (BMM) is an established "site of sanctuary" for ALL, as well as myeloid-lineage hematopoietic disease, with signals in this unique anatomic location contributing to drug resistance. Several models have been developed to recapitulate the interactions between the BMM and ALL cells. However, many in vitro models fail to accurately reflect the level of protection afforded to the most resistant subset of leukemic cells during coculture with BMM elements. Preclinical in vivo models have advantages, but can be costly, and are often not fully informed by optimal in vitro studies. We describe an innovative extension of 2-D coculture wherein ALL cells uniquely interact with bone marrow-derived stromal cells. Tumor cells in this model bury beneath primary human bone marrow-derived stromal cells or osteoblasts, termed "phase dim" ALL, and exhibit a unique phenotype characterized by altered metabolism, distinct protein expression profiles, increased quiescence, and pronounced chemotherapy resistance. Investigation focused on the phase dim subpopulation may more efficiently inform preclinical design and investigation of the minimal residual disease and relapse that arise from BMM-supported leukemic tumor cells.
authors.affiliation: Alexander B. Osborn Hematopoietic Malignancy and Transplantation Program of the Mary Babb Randolph Cancer Center, Robert C. Byrd Health Sciences Center, West Virginia University School of Medicine, Morgantown, WV.
authors.forename: Blake S
authors.initials: BS
authors.lastname: Moses
authors.affiliation: Alexander B. Osborn Hematopoietic Malignancy and Transplantation Program of the Mary Babb Randolph Cancer Center, Robert C. Byrd Health Sciences Center, West Virginia University School of Medicine, Morgantown, WV.
authors.forename: William L
authors.initials: WL
authors.lastname: Slone
authors.affiliation: Alexander B. Osborn Hematopoietic Malignancy and Transplantation Program of the Mary Babb Randolph Cancer Center, Robert C. Byrd Health Sciences Center, West Virginia University School of Medicine, Morgantown, WV.
authors.forename: Patrick
authors.initials: P
authors.lastname: Thomas
authors.affiliation: Alexander B. Osborn Hematopoietic Malignancy and Transplantation Program of the Mary Babb Randolph Cancer Center, Robert C. Byrd Health Sciences Center, West Virginia University School of Medicine, Morgantown, WV.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Evans
authors.affiliation: Alexander B. Osborn Hematopoietic Malignancy and Transplantation Program of the Mary Babb Randolph Cancer Center, Robert C. Byrd Health Sciences Center, West Virginia University School of Medicine, Morgantown, WV.
authors.forename: Debbie
authors.initials: D
authors.lastname: Piktel
authors.affiliation: Protea Bioscience, Morgantown, WV.
authors.forename: Peggi M
authors.initials: PM
authors.lastname: Angel
authors.affiliation: Protea Bioscience, Morgantown, WV.
authors.forename: Callee M
authors.initials: CM
authors.lastname: Walsh
authors.affiliation: Protea Bioscience, Morgantown, WV.
authors.forename: Pamela S
authors.initials: PS
authors.lastname: Cantrell
authors.affiliation: Department of Physiology & Pharmacology, West Virginia University School of Medicine, Morgantown, WV.
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Rellick
authors.affiliation: Alexander B. Osborn Hematopoietic Malignancy and Transplantation Program of the Mary Babb Randolph Cancer Center, Robert C. Byrd Health Sciences Center, West Virginia University School of Medicine, Morgantown, WV; Department of Neurobiology and Anatomy, West Virginia University School of Medicine, Morgantown, WV.
authors.forename: Karen H
authors.initials: KH
authors.lastname: Martin
authors.affiliation: Department of Physiology & Pharmacology, West Virginia University School of Medicine, Morgantown, WV; Center for Basic and Translational Stroke Research, West Virginia University School of Medicine, Morgantown, WV; Center for Neuroscience, West Virginia University School of Medicine, Morgantown, WV.
authors.forename: James W
authors.initials: JW
authors.lastname: Simpkins
authors.affiliation: Alexander B. Osborn Hematopoietic Malignancy and Transplantation Program of the Mary Babb Randolph Cancer Center, Robert C. Byrd Health Sciences Center, West Virginia University School of Medicine, Morgantown, WV; Department of Microbiology, Immunology and Cell Biology, Robert C. Byrd Health Sciences Center, West Virginia University School of Medicine, Morganstown, WV. Electronic address: lgibson@hsc.wvu.edu.
authors.forename: Laura F
authors.initials: LF
authors.lastname: Gibson
mesh_terms: D001853:Bone Marrow / Q000473:pathology*; D018920:Coculture Techniques; D006801:Humans; D010641:Phenotype; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000473:pathology*; D059016:Tumor Microenvironment