The lymph node microenvironment promotes B-cell receptor signaling, NF-κB activation, and tumor proliferation in chronic lymphocytic leukemia

Herishanu, Yair; Pérez-Galán, Patricia; Liu, Delong; Biancotto, Angélique; Pittaluga, Stefania; Vire, Bérengère; Gibellini, Federica; Njuguna, Ndegwa; Lee, Elinor; Stennett, Lawrence; Raghavachari, Nalini; Liu, Poching; McCoy, J. Philip; Raffeld, Mark; Stetler‐Stevenson, Maryalice; Yuan, Constance; Sherry, Richard M.; Arthur, Diane C.; Marić, Irina; White, Therese; Marti, Gerald E.; Munson, Peter J.; Wilson, Wyndham H.; Wiestner, Adrian

doi:10.1182/blood-2010-05-284984

Cited by 767 publications

(994 citation statements)

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“…7 There, we utilized NLC, a model resembling CLL cell exposure to the lymphatic tissue microenvironment. NLC-induced GE changes are remarkably similar to GE profiles of CLL cells isolated from CLL lymph nodes in vivo, 8 emphasizing the validity of this approach. To expand on these findings and to test whether stroma cell exposure induces modulation of key survival genes with largely unknown mode of regulation in CLL, such as the T-cell leukemia/ lymphoma 1 (TCL1) proto-oncogene, we analyzed GE changes in purified CLL cells during co-culture with mesenchymal bone marrow stromal cells (BMSC).…”

Section: Introductionmentioning

confidence: 70%

“…3 In the tissue compartments, CLL cells engage in complex cellular and molecular interactions with accessory cells, collectively referred to as the CLL microenvironment (reviewed in Burger et al 4 ). For example, in the lymphatic tissues, CLL cells interact with T cells 5 and CD68 þ , monocytederived nurse-like cells (NLC), 6 and display signs of B-cell antigen receptor (BCR) activation, 7,8 suggesting that CLL cell proliferation is BCR-and T-cell driven.…”

Section: Introductionmentioning

confidence: 99%

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Stromal cells modulate TCL1 expression, interacting AP-1 components and TCL1-targeting micro-RNAs in chronic lymphocytic leukemia

et al. 2012

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The tissue microenvironment in chronic lymphocytic leukemia (CLL) has an increasingly recognized role in disease progression, but the molecular mechanisms of cross talk between CLL cells and their microenvironment remain incompletely defined. Bone marrow stromal cells (BMSC) protect CLL cells from apoptosis in a contact-dependent fashion, and have been used for the identification of key pathways such as the CXCR4 --CXCL12 axis. To further dissect the molecular impact of BMSC on survival and the molecular activation signature of CLL cells, we co-cultured CLL cells with different BMSC. Gene expression profiling of CLL cells revealed that the lymphoid proto-oncogene TCL1 was among the top genes upregulated in CLL cells by BMSC. TCL1 mRNA and protein upregulation by BMSC was paralleled by decreases of TCL1-interacting FOS/JUN, and confirmed by qRT-PCR, immunoblotting, immunoprecipitations, and flow cytometry. Stroma mediated increases in TCL1 were also associated with decreased levels of TCL1-regulatory micro-RNAs (miR-29b, miR-181b, miR-34b). These findings demonstrate that the microenvironment has a proactive role in the regulation of the known signaling enhancer and pro-survival molecule TCL1 in CLL. This provides a further rationale for therapeutically targeting the cross talk between CLL and BMSC.

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Section: Introductionmentioning

confidence: 70%

Section: Introductionmentioning

confidence: 99%

Stromal cells modulate TCL1 expression, interacting AP-1 components and TCL1-targeting micro-RNAs in chronic lymphocytic leukemia

et al. 2012

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“…Further underscoring the role of BCR in mature B-cell malignancies, a strict dependency on a specific BCR engagement has been shown for activated B-cell (ABC) DLBCL cell lines [71]. Expression profiling associated BCR signaling-like signatures with aggressive disease, in both general CLL cohorts and specific subsets [72][73][74]. In addition, prominent intracellular signaling is observed in CLL cells from or egressing from lymph node, suggesting that lymph nodes are sites of survival and proliferative stimulus [72].…”

Section: Implication Of the Bcr Tlr Pathwaysmentioning

confidence: 94%

Chronic lymphocytic leukemia: Time to go past genomics?

2016

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Recent advances in massively parallel sequencing technologies have provided a detailed picture of the mutational landscape in CLL and underscored the vast degree of interpatient and intratumor heterogeneities. These studies have led to the characterization of novel putative driver genes and recurrently affected biological pathways, and to the modeling of CLL clonal evolution. We herein review selected aspects including recent advances in the biology of CLL and present cellular and biological processes involved in the development of CLL and potentially other mature B-cell lymphoproliferative neoplasms.

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“…Within lymphoid tissues, CLL cells receive activation and proliferation stimuli from the microenvironment before being released into the peripheral blood, where they undergo accumulation, as apoptosis does not counterbalance previous proliferation. [1][2][3] Drugs that are both cytotoxic on cycling CLL cells and able to affect CLLs' apoptosis resistance would be greatly beneficial in the treatment of this disease.…”

Section: Introductionmentioning

confidence: 99%

N-(4-hydroxyphenyl)retinamide promotes apoptosis of resting and proliferating B-cell chronic lymphocytic leukemia cells and potentiates fludarabine and ABT-737 cytotoxicity

et al. 2012

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The lymph node microenvironment promotes B-cell receptor signaling, NF-κB activation, and tumor proliferation in chronic lymphocytic leukemia

Cited by 767 publications

References 52 publications

Stromal cells modulate TCL1 expression, interacting AP-1 components and TCL1-targeting micro-RNAs in chronic lymphocytic leukemia

Stromal cells modulate TCL1 expression, interacting AP-1 components and TCL1-targeting micro-RNAs in chronic lymphocytic leukemia

Chronic lymphocytic leukemia: Time to go past genomics?

N-(4-hydroxyphenyl)retinamide promotes apoptosis of resting and proliferating B-cell chronic lymphocytic leukemia cells and potentiates fludarabine and ABT-737 cytotoxicity

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