TY - JOUR
T1 - Diverse marrow stromal cells protect CLL cells from spontaneous and drug-induced apoptosis
T2 - Development of a reliable and reproducible system to assess stromal cell adhesion-mediated drug resistance
AU - Kurtova, Antonina V.
AU - Balakrishnan, Kumudha
AU - Chen, Rong
AU - Ding, Wei
AU - Schnabl, Susanne
AU - Quiroga, Maite P.
AU - Sivina, Mariela
AU - Wierda, William G.
AU - Estrov, Zeev
AU - Keating, Michael J.
AU - Shehata, Medhat
AU - Jäger, Ulrich
AU - Gandhi, Varsha
AU - Kay, Neil E.
AU - Plunkett, William
AU - Burger, Jan A.
PY - 2009/11/12
Y1 - 2009/11/12
N2 - 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 cyclo-phosphamide-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.
AB - 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 cyclo-phosphamide-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.
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U2 - 10.1182/blood-2009-07-233718
DO - 10.1182/blood-2009-07-233718
M3 - Article
C2 - 19762485
AN - SCOPUS:73349126115
SN - 0006-4971
VL - 114
SP - 4441
EP - 4450
JO - Blood
JF - Blood
IS - 20
ER -