Lymph node‐induced immune tolerance in chronic lymphocytic leukaemia: a role for caveolin‐1

Gilling, Christine E; Mittal, Amit; Chaturvedi, Nagendra K.; Iqbal, Javeed; Aoun, Patricia; Bierman, Philip J.; Bociek, R. Gregory; Weisenburger, Dennis D.; Joshi, Shantaram S.

doi:10.1111/j.1365-2141.2012.09148.x

Cited by 33 publications

(51 citation statements)

References 66 publications

(91 reference statements)

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“…Interestingly, genes associated with immune tolerogenesis (CAV1, MCM3, BATF) were uniquely overexpressed in LN-CLL compared with BM-CLL and PB-CLL ( Figures 2B and 3, Supplementary Figure S1), indicating the LN microenvironment plays a role in inducing immunological tolerance of CLL cells. The role of this tolerogenic signature in LN is recently validated by us (38). Together, these results elucidate the genes overexpressed in LN-CLL and indicate that the microenvironment influences CLL cell behavior.…”

Section: Differentially Expressed Genes Associated With the Seven Majsupporting

confidence: 55%

“…One explanation for this phenomenon is that the immune-suppressive gene signature expressed by CLL cells creates immune dysfunction in the LN site and, thus, may contribute to immune evasion of CLL cells in this site. These genes may play a crucial role in modulating T-cell behavior and immune synapse formation for the benefit of CLL cells (38,39). Because BLA is used as a marker of aggressive disease (21), we correlated GEPs with the presence and absence of BLA in PB.…”

Section: Discussionmentioning

confidence: 99%

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Chronic Lymphocytic Leukemia Cells in a Lymph Node Microenvironment Depict Molecular Signature Associated with an Aggressive Disease

Mittal

Chaturvedi

Karan

et al. 2014

Mol Med

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Chronic lymphocytic leukemia (CLL) cells survive longer in vivo than in vitro, suggesting that the tissue microenvironment provides prosurvival signals to tumor cells. Primary and secondary lymphoid tissues are involved in the pathogenesis of CLL, and the role of these tissue microenvironments has not been explored completely. To elucidate host-tumor interactions, we performed gene expression profiling (GEP) of purified CLL cells from peripheral blood (PB; n = 20), bone marrow (BM; n = 18), and lymph node (LN; n = 15) and validated key pathway genes by real-time polymerase chain reaction, immunohistochemistry and/or TCL1 transgenic mice. Gene signatures representing several pathways critical for survival and activation of B cells were altered in CLL cells from different tissue compartments. Molecules associated with the B-cell receptor (BCR), B cell-activating factor/a proliferationinducing ligand (BAFF/APRIL), nuclear factor (NF)-κB pathway and immune suppression signature were enriched in LN-CLL, suggesting LNs as the primary site for tumor growth. Immune suppression genes may help LN-CLL cells to modulate antigenpresenting and T-cell behavior to suppress antitumor activity. PB CLL cells overexpressed chemokine receptors, and their cognate ligands were enriched in LN and BM, suggesting that a chemokine gradient instructs B cells to migrate toward LN or BM. Of several chemokine ligands, the expression of CCL3 was associated with poor prognostic factors. The BM gene signature was enriched with antiapoptotic, cytoskeleton and adhesion molecules. Interestingly, PB cells from lymphadenopathy patients shared GEP with LN cells. In Eμ-TCL1 transgenic mice (the mouse model of the disease), a high percentage of leukemic cells from the lymphoid compartment express key BCR and NF-κB molecules. Together, our findings demonstrate that the lymphoid microenvironment promotes survival, proliferation and progression of CLL cells via chronic activation of BCR, BAFF/APRIL and NF-κB activation while suppressing the immune response.

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Section: Differentially Expressed Genes Associated With the Seven Majsupporting

confidence: 55%

Section: Discussionmentioning

confidence: 99%

Chronic Lymphocytic Leukemia Cells in a Lymph Node Microenvironment Depict Molecular Signature Associated with an Aggressive Disease

Mittal

Chaturvedi

Karan

et al. 2014

Mol Med

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“…Furthermore, Joshi et al [79] defined a feedback loop between Rho/ROCK, Src, and phosphorylated CAV1 in tumor cell protrusions, identifying a novel function for CAV1 in tumor metastasic spreading. More interestingly perhaps, Gilling et al [80] recently described a critical role for CAV1 in CLL progression involving CLL-tumor microenvironment interaction, specifically immune synapse formation, migration, and proliferation.…”

Section: Discussionmentioning

confidence: 99%

Chromosome 2p gain in monoclonal B‐cell lymphocytosis and in early stage chronic lymphocytic leukemia

et al. 2012

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Recent studies have described chromosome 2p gain as a recurrent lesion in chronic lymphocytic leukemia (CLL). We investigated the 2p gain and its relationship with common prognostic biomarkers in a prospective series of 69 clinical monoclonal B-cell lymphocytosis (cMBL) and 218 early stage (Binet A) CLL patients. The 2p gain was detected by FISH in 17 patients (6%, 16 CLL, and 1 cMBL) and further characterized by single nucleotide polymorphism-array. Overall, unfavorable cytogenetic deletions, i.e., del(11)(q23) and del(17)(p13) (P 5 0.002), were significantly more frequent in 2p gain cases, as well as unmutated status of IGHV (P < 1 3 10 24 ) and CD38 (P < 1 3 10 24 ) and ZAP-70 positive expression (P 5 0.003). Furthermore, 2p gain patients had significantly higher utilization of stereotyped B-cell receptors compared with 2p negative patients (P 5 0.009), and the incidence of stereotyped subset #1 in 2p gain patients was significantly higher than that found in the remaining CLLs (P 5 0.031). Transcriptional profiling analysis identified several genes significantly upregulated in 2p gain CLLs, most of which mapped to 2p. Among these, NCOA1 and ROCK2 are known for their involvement in tumor progression in several human cancers, whereas among those located in different chromosomes, CAV1 at 7q31.1 has been recently identified to play a critical role in CLL progression. Thus, 2p gain can be present since the early stages of the disease, particularly in those cases characterized by other poor prognosis markers. The finding of genes upregulated in the cells with 2p gain provides new insights to define the pathogenic role of this lesion. Am. J. Hematol. 88:24-31, 2013. V

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“…Some genes comprising a "tolerogenic signature" for CLL 28,29 were also upregulated on transgenic CD19…”

Section: Impaired Receptor Editing Promotes Cll Progression 3859mentioning

confidence: 99%

Accelerated progression of chronic lymphocytic leukemia in Eμ-TCL1 mice expressing catalytically inactive RAG1

Nganga

Palmer

Naushad

et al. 2013

Blood

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Lymph node‐induced immune tolerance in chronic lymphocytic leukaemia: a role for caveolin‐1

Cited by 33 publications

References 66 publications

Chronic Lymphocytic Leukemia Cells in a Lymph Node Microenvironment Depict Molecular Signature Associated with an Aggressive Disease

Chronic Lymphocytic Leukemia Cells in a Lymph Node Microenvironment Depict Molecular Signature Associated with an Aggressive Disease

Chromosome 2p gain in monoclonal B‐cell lymphocytosis and in early stage chronic lymphocytic leukemia

Accelerated progression of chronic lymphocytic leukemia in Eμ-TCL1 mice expressing catalytically inactive RAG1

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