Clinical Heterogeneity of CLL: Role for Immune Dysregulation Mediated by the Lymph Node Microenvironment.

Mittal, Amit; Gilling, Christine E; Iqbal, Javeed; Bociek, R. Gregory; Aoun, Patricia; Bierman, Philip J.; Joshi, Shantaram S.

doi:10.1182/blood.v114.22.1243.1243

Cited by 3 publications

(2 citation statements)

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“…Virtual extracellular environments, composed of 20 CD4 + T-cell stimuli, were optimized for each in silico experiment based on immunocompetent versus immunocompromised (diseased) settings [Table 1 ; Ref. ( 9 , 13 , 30 , 31 , 34 , 35 )]. For each experiment, these values were analyzed and used to compare proteins most affected by CAV1 +/+ , CAV1 +/− , and CAV1 −/− in an immunocompetent (i.e., WT) versus varying degrees of immunosuppression (i.e., Diseases A versus B) condition.…”

Section: Methodsmentioning

confidence: 99%

Design, Assessment, and in vivo Evaluation of a Computational Model Illustrating the Role of CAV1 in CD4+ T-lymphocytes

et al. 2014

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Caveolin-1 (CAV1) is a vital scaffold protein heterogeneously expressed in both healthy and malignant tissue. We focus on the role of CAV1 when overexpressed in T-cell leukemia. Previously, we have shown that CAV1 is involved in cell-to-cell communication, cellular proliferation, and immune synapse formation; however, the molecular mechanisms have not been elucidated. We hypothesize that the role of CAV1 in immune synapse formation contributes to immune regulation during leukemic progression, thereby warranting studies of the role of CAV1 in CD4+ T-cells in relation to antigen-presenting cells. To address this need, we developed a computational model of a CD4+ immune effector T-cell to mimic cellular dynamics and molecular signaling under healthy and immunocompromised conditions (i.e., leukemic conditions). Using the Cell Collective computational modeling software, the CD4+ T-cell model was constructed and simulated under CAV1+/+, CAV1+/−, and CAV1−/− conditions to produce a hypothetical immune response. This model allowed us to predict and examine the heterogeneous effects and mechanisms of CAV1 in silico. Experimental results indicate a signature of molecules involved in cellular proliferation, cell survival, and cytoskeletal rearrangement that were highly affected by CAV1 knock out. With this comprehensive model of a CD4+ T-cell, we then validated in vivo protein expression levels. Based on this study, we modeled a CD4+ T-cell, manipulated gene expression in immunocompromised versus competent settings, validated these manipulations in an in vivo murine model, and corroborated acute T-cell leukemia gene expression profiles in human beings. Moreover, we can model an immunocompetent versus an immunocompromised microenvironment to better understand how signaling is regulated in patients with leukemia.

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Section: Methodsmentioning

confidence: 99%

Design, Assessment, and in vivo Evaluation of a Computational Model Illustrating the Role of CAV1 in CD4+ T-lymphocytes

et al. 2014

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“…Microarray analyses were used to determine differential expression of genes in a region of 13q suggested to be deleted in CLL [8,9]. Previously, a tolerogenic signature was associated with poor prognosis in CLL [9][10][11][12]. Genes from the tolerogenic signature were examined among patients with 13q null, 13q mono, and WT cases.…”

Section: Fluorescent In Situ Hybridization [Fish]mentioning

confidence: 99%

Polycomb response element-binding sites in the MDR of CLL: Potential tumor suppressor regulation

Cutucache¹,

Iqbal²,

Bierman³

et al. 2013

ABB

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Chronic lymphocytic leukemia [CLL] is the most common adult leukemia and is heterogeneous in clinical presentation. CLL cases present with various chromosomal aberrations, including 11q23, 14q32, 17p, and trisomy 12, with the most common abnormality being deletion of 13q14 [1]. Although monoallelic deletion of 13q14 is common, there is a subset of patients who have complete nullisomy at 13q14, a locus that has been hypothesized to contribute to CLL pa thogenesis [2] due to loss of tumor suppressors [DLEU and miR-15a/16-1]. We hypothesized that deletion of both copies of 13q14 would lead to uncontrollable proliferation of CLL cells and a poor prognosis. We examined our 13q14 nullisomy for survival, treatment-free survival, lymphocyte doubling time, and the presence of lymphadenopathy. Furthermore, we compared the gene expression profiles between patients with 13q14 monosomy, nullisomy, or normal karyotype. Our results suggest that patients with 13q nullisomy have a higher incidence of bulky lymphadenopathy [16.6% compared to 10% of monosomy patients], a higher frequency of lymphocyte doubling time [27.7% compared to 7.4% of monosomy patients], and a higher rate of needing treatment [50% compared to 18.5% of monosomy patients]. We observed deletion of DLEU1 and HTR2A, consistent with a gene dosage effect, and observed PRE-binding sites on DLEU1. Patients with homozygous deletion of 13q14 had a worse prognosis compared to heterozygotes. Lastly, the DLEU1 locus is a possible “second hit” loss for CLL progression.

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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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Clinical Heterogeneity of CLL: Role for Immune Dysregulation Mediated by the Lymph Node Microenvironment.

Cited by 3 publications

References 0 publications

Design, Assessment, and in vivo Evaluation of a Computational Model Illustrating the Role of CAV1 in CD4+ T-lymphocytes

Design, Assessment, and in vivo Evaluation of a Computational Model Illustrating the Role of CAV1 in CD4+ T-lymphocytes

Polycomb response element-binding sites in the MDR of CLL: Potential tumor suppressor regulation

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

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