title: Diverse marrow stromal cells protect CLL cells from spontaneous and drug-induced apoptosis: development of a reliable and reproducible system to assess stromal cell adhesion-mediated drug resistance.
abstract: Marrow stromal cells (MSCs) provide important survival and drug resistance signals to chronic lymphocytic leukemia (CLL) cells, but current models to analyze CLL-MSC interactions are heterogeneous. Therefore, we tested different human and murine MSC lines and primary human MSCs for their ability to protect CLL cells from spontaneous and drug-induced apoptosis. Our results show that both human and murine MSCs are equally effective in protecting CLL cells from fludarabine-induced apoptosis. This protective effect was sustained over a wide range of CLL-MSC ratios (5:1 to 100:1), and the levels of protection were reproducible in 4 different laboratories. Human and murine MSCs also protected CLL cells from dexamethasone- and cyclophosphamide-induced apoptosis. This protection required cell-cell contact and was virtually absent when CLL cells were separated from the MSCs by micropore filters. Furthermore, MSCs maintained Mcl-1 and protected CLL cells from spontaneous and fludarabine-induced Mcl-1 and PARP cleavage. Collectively, these studies define common denominators for CLL cocultures with MSCs. They also provide a reliable, validated tool for future investigations into the mechanism of MSC-CLL cross talk and for drug testing in a more relevant fashion than the commonly used suspension cultures.
authors.affiliation: Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77230-1402, USA.
authors.forename: Antonina V
authors.initials: AV
authors.lastname: Kurtova
authors.forename: Kumudha
authors.initials: K
authors.lastname: Balakrishnan
authors.forename: Rong
authors.initials: R
authors.lastname: Chen
authors.forename: Wei
authors.initials: W
authors.lastname: Ding
authors.forename: Susanne
authors.initials: S
authors.lastname: Schnabl
authors.forename: Maite P
authors.initials: MP
authors.lastname: Quiroga
authors.forename: Mariela
authors.initials: M
authors.lastname: Sivina
authors.forename: William G
authors.initials: WG
authors.lastname: Wierda
authors.forename: Zeev
authors.initials: Z
authors.lastname: Estrov
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Keating
authors.forename: Medhat
authors.initials: M
authors.lastname: Shehata
authors.forename: Ulrich
authors.initials: U
authors.lastname: Jäger
authors.forename: Varsha
authors.initials: V
authors.lastname: Gandhi
authors.forename: Neil E
authors.initials: NE
authors.lastname: Kay
authors.forename: William
authors.initials: W
authors.lastname: Plunkett
authors.forename: Jan A
authors.initials: JA
authors.lastname: Burger
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D002448:Cell Adhesion / Q000502:physiology; D002450:Cell Communication / Q000502:physiology*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D018920:Coculture Techniques; D019008:Drug Resistance, Neoplasm; D005434:Flow Cytometry; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D017154:Stromal Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents