Involvement of p53 in α4β1 integrin-mediated resistance of B-CLL cells to fludarabine

Fuente, M. T. de la; Casanova, Benito; Cantero, Esperanza; Cerro, Mercedes Hernández del; García-Marco, José A.; Silva, Augusto; García-Pardo, Ángeles

doi:10.1016/j.bbrc.2003.10.054

Cited by 35 publications

(26 citation statements)

References 29 publications

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“…Further work is ongoing to identify the factor(s) since maneuvers to reduce the activity or levels of the protective factor may augment the efficacy of some therapeutic approaches. Similar to other investigators [36,37], we have not seen the same kind of protection with MSE soluble factors for CLL B-cells exposed to fludarabine where physical contact between stroma and CLL B-cells appears to be necessary for protection to occur (data not shown). Therefore, the mechanisms by which MSE protect CLL B-cells from drug induced death appears to depend to a certain extent on the drugs mechanism of action.…”

Section: Discussionsupporting

confidence: 74%

Bone biopsy derived marrow stromal elements rescue chronic lymphocytic leukemia B-cells from spontaneous and drug induced cell death and facilitates an “angiogenic switch”

et al. 2007

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A novel bone biopsy technique was used to generate a robust stromal cell system to study how stroma modulates CLL B-cell apoptosis and how the leukemic cell-stromal interaction influences secretion of vascular factors. Marrow stromal elements (MSE) rescued CLL B-cells from both spontaneous and drug induced apoptosis, partly due to soluble factors. When CLL B-cells were added to the MSE cultures, a dramatic increase in the secretion of basic fibroblast growth factor and decrease in the secretion of thrombospondin was observed. These results indicate the interaction between CLL Bcells and marrow stromal elements regulates angiogenic switching and may be linked to disease progression.

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Section: Discussionsupporting

confidence: 74%

Bone biopsy derived marrow stromal elements rescue chronic lymphocytic leukemia B-cells from spontaneous and drug induced cell death and facilitates an “angiogenic switch”

et al. 2007

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“…It is well established that fludarabine induces p53 expression 22 and we have shown that interfering with this expression by crosslinking a4b1 integrin induces cell survival. 23 In results not shown, we did not observe induction of p53 in the present study, thus ruling out a role for this protein in the AT514 apoptotic pathway.…”

Section: Discussioncontrasting

confidence: 55%

AT514, a cyclic depsipeptide from Serratia marcescens, induces apoptosis of B-chronic lymphocytic leukemia cells: interference with the Akt/NF-κB survival pathway

et al. 2005

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Clinical treatment of B-cell chronic lymphocytic leukemia (B-CLL) is limited by the progressive drug resistance and nonselectivity of most drugs towards malignant cells. Depsipeptides are present in certain bacteria and display potent antitumor activity. We have studied the effect of the novel cyclodepsipeptide AT514 (serratamolide) from Serratia marcescens on B-CLL cell viability. AT514 induced apoptosis of B-CLL cells from the 21 patients studied, as confirmed by Annexin-V binding and nuclei condensation, with an average IC 50 of 13 lM. AT514 was effective in those B-CLL cases resistant to fludarabine, but had no effect on normal PBL. AT514 preferentially activated the intrinsic apoptotic pathway, as evidenced by loss of mitochondrial membrane potential, release of cytochrome c and activation of caspase-9 and -3, but not of caspase-8. Importantly, AT514 interfered with phosphatidylinositol-3 kinase and protein kinase C survival signals since it increased the apoptotic effect of LY294002 and BisI inhibitors, and induced Akt dephosphorylation at Ser 473. AT514 also decreased NF-jB activity by dramatically reducing the levels of p65 in B-CLL. This was confirmed on functional assays using NF-jB-luc-transfected Raji cells and transgenic mice. Our results establish that AT514 induces apoptosis of primary B-CLL cells and could be useful for clinical treatment of this malignancy.

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“…4,6 Bone marrow stromal cells have been shown to protect normal and malignant hematopoietic cells from damaging events, including drug-induced cell death. [7][8][9][10][11][12] Normal hematopoiesis is regulated by the adhesive interaction of hematopoietic cells with the bone marrow microenvironment, as well as by growth factors and cytokines expressed by different types of bone marrow cells. 12 The bone marrow microenvironment consists of stromal cells and extracellular matrix proteins such as fibronectin, collagen and laminin.…”

Section: Introductionmentioning

confidence: 99%

High VLA-4 expression is associated with adverse outcome and distinct gene expression changes in childhood B-cell precursor acute lymphoblastic leukemia at first relapse

Shalapour¹,

Hof²,

Kirschner-Schwabe³

et al. 2011

Haematologica

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The online version of this article has a Supplementary Appendix. BackgroundResistance to therapy and subsequent relapse remain major challenges in the clinical management of relapsed childhood acute lymphoblastic leukemia. As the bone marrow environment plays an important role in survival and chemotherapy resistance of leukemia cells by activating different signaling pathways, such as the VLA-4 and PI3K/Akt pathways, we studied the prognostic and biological impact of VLA-4 expression in leukemia cells from children with relapsed B-cell precursor acute lymphoblastic leukemia and its influence on the sensitivity of the leukemia cells to drugs. Design and MethodsVLA-4 expression was quantified by real-time polymerase chain reaction in leukemia cells from 56 patients with relapsed acute lymphoblastic leukemia enrolled in the ALL-REZ BFM 2002 trial of the Berlin-Frankfurt-Münster study group. Gene expression changes related to VLA-4 expression were investigated by microarray-based mRNA profiling. The effect of VLA-4 signaling on proliferation and drug resistance was studied in co-cultures of leukemia and stromal cells. ResultsHigh expression of VLA-4 at first relapse was associated with adverse prognostic factors, poor molecular response to therapy and significantly worse probabilities of event-free and overall survival. VLA-4 expression was an independent prognostic parameter. Comparing gene expression profiles of leukemia cells with high versus low VLA-4 expression, we identified 27 differentially expressed genes primarily involved in the PI3K/Akt, ephrin and Rho GTPase pathways. Blocking of VLA-4 signaling in combination with cytarabine treatment abolished the growth supportive effect of stromal cells. ConclusionsOur results show that high VLA-4 expression is a marker of poor prognosis and a potential therapeutic target in children with relapsed acute lymphoblastic leukemia and confirm that cellular interactions and biological effects related to VLA-4 play a decisive role in the survival of leukemia cells and response to therapy. (ClinicalTrials.gov identifier: NCT00114348)

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Involvement of p53 in α4β1 integrin-mediated resistance of B-CLL cells to fludarabine

Cited by 35 publications

References 29 publications

Bone biopsy derived marrow stromal elements rescue chronic lymphocytic leukemia B-cells from spontaneous and drug induced cell death and facilitates an “angiogenic switch”

Bone biopsy derived marrow stromal elements rescue chronic lymphocytic leukemia B-cells from spontaneous and drug induced cell death and facilitates an “angiogenic switch”

AT514, a cyclic depsipeptide from Serratia marcescens, induces apoptosis of B-chronic lymphocytic leukemia cells: interference with the Akt/NF-κB survival pathway

High VLA-4 expression is associated with adverse outcome and distinct gene expression changes in childhood B-cell precursor acute lymphoblastic leukemia at first relapse

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