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

Antonina V. Kurtova, Kumudha Balakrishnan, Rong Chen, Wei D Ding, Susanne Schnabl, Maite P. Quiroga, Mariela Sivina, William G. Wierda, Zeev Estrov, Michael J. Keating, Medhat Shehata, Ulrich Jäger, Varsha Gandhi, Neil Elliot Kay, William Plunkett, Jan A. Burger

Research output: Contribution to journalArticle

208 Citations (Scopus)

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 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.

Original languageEnglish (US)
Pages (from-to)4441-4450
Number of pages10
JournalBlood
Volume114
Issue number20
DOIs
StatePublished - Nov 12 2009

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Cell adhesion
B-Cell Chronic Lymphocytic Leukemia
Stromal Cells
Drug Resistance
Cell Adhesion
Bone Marrow
Apoptosis
Dimethoate
Pharmaceutical Preparations
Dexamethasone
Suspensions
Cells
Testing
Micropore Filters
Cytoprotection
fludarabine
Coculture Techniques
Cell Communication
Cell Line

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

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. / Kurtova, Antonina V.; Balakrishnan, Kumudha; Chen, Rong; Ding, Wei D; Schnabl, Susanne; Quiroga, Maite P.; Sivina, Mariela; Wierda, William G.; Estrov, Zeev; Keating, Michael J.; Shehata, Medhat; Jäger, Ulrich; Gandhi, Varsha; Kay, Neil Elliot; Plunkett, William; Burger, Jan A.

In: Blood, Vol. 114, No. 20, 12.11.2009, p. 4441-4450.

Research output: Contribution to journalArticle

Kurtova, AV, Balakrishnan, K, Chen, R, Ding, WD, Schnabl, S, Quiroga, MP, Sivina, M, Wierda, WG, Estrov, Z, Keating, MJ, Shehata, M, Jäger, U, Gandhi, V, Kay, NE, Plunkett, W & Burger, JA 2009, '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', Blood, vol. 114, no. 20, pp. 4441-4450. https://doi.org/10.1182/blood-2009-07-233718
Kurtova, Antonina V. ; Balakrishnan, Kumudha ; Chen, Rong ; Ding, Wei D ; Schnabl, Susanne ; Quiroga, Maite P. ; Sivina, Mariela ; Wierda, William G. ; Estrov, Zeev ; Keating, Michael J. ; Shehata, Medhat ; Jäger, Ulrich ; Gandhi, Varsha ; Kay, Neil Elliot ; Plunkett, William ; Burger, Jan A. / 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. In: Blood. 2009 ; Vol. 114, No. 20. pp. 4441-4450.
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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 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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AU - Kurtova, Antonina V.

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AU - Chen, Rong

AU - Ding, Wei D

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 Elliot

AU - Plunkett, William

AU - Burger, Jan A.

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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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