title: Stromal-mediated protection of tyrosine kinase inhibitor-treated BCR-ABL-expressing leukemia cells.
abstract: Clinical studies of patients with chronic myeloid leukemia revealed that a common pattern of response is a dramatic fall in the circulating population of blast cells, with a minimal or delayed decrease in marrow blasts, suggesting a protective environment. These observations suggest that a greater understanding of the interaction of stromal cells with leukemic cells is essential. Here, we present an in vivo system for monitoring relative tumor accumulation in leukemic mice and residual disease in leukemic mice treated with a tyrosine kinase inhibitor and an in vitro system for identifying integral factors involved in stromal-mediated cytoprotection. Using the in vivo model, we observed high tumor burden/residual disease in tissues characterized as significant sources of hematopoiesis-promoting stroma, with bone marrow stroma most frequently showing the highest accumulation of leukemia in untreated and nilotinib-treated mice as well as partial protection of leukemic cells from the inhibitory effects of nilotinib. These studies, which showed a pattern of leukemia distribution consistent with what is observed in imatinib- and nilotinib-treated chronic myeloid leukemia patients, were followed by a more in-depth analysis of stroma-leukemia cell interactions that lead to protection of leukemia cells from nilotinib-induced cytotoxicity. For the latter, we used the human BCR-ABL-positive cell line, KU812F, and the human bone marrow stroma cell line, HS-5, to more closely approximate the bone marrow-associated cytoprotection observed in drug-treated leukemia patients. This in vitro system helped to elucidate stromal-secreted viability factors that may play a role in stromal-mediated cytoprotection of tyrosine kinase inhibitor-treated leukemia cells.
authors.affiliation: Department of Medical Oncology/Hematologic Neoplasia, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115, USA. Ellen_Weisberg@dfci.harvard.edu
authors.forename: Ellen
authors.initials: E
authors.lastname: Weisberg
authors.forename: Renee D
authors.initials: RD
authors.lastname: Wright
authors.forename: Douglas W
authors.initials: DW
authors.lastname: McMillin
authors.forename: Constantine
authors.initials: C
authors.lastname: Mitsiades
authors.forename: Arghya
authors.initials: A
authors.lastname: Ray
authors.forename: Rosemary
authors.initials: R
authors.lastname: Barrett
authors.forename: Sophia
authors.initials: S
authors.lastname: Adamia
authors.forename: Richard
authors.initials: R
authors.lastname: Stone
authors.forename: Ilene
authors.initials: I
authors.lastname: Galinsky
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Kung
authors.forename: James D
authors.initials: JD
authors.lastname: Griffin
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use / Q000633:toxicity*; D001854:Bone Marrow Cells / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D047428:Protein Kinase Inhibitors / Q000378:metabolism / Q000633:toxicity*; D011743:Pyrimidines / Q000633:toxicity; D017154:Stromal Cells / Q000502:physiology
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D016044:Fusion Proteins, bcr-abl; C498826:nilotinib