Zheng, Z., Venkatapathy, S., Rao, G. & Harrington, C.A. Expression profiling of B cell chronic lymphocytic leukemia suggests deficient CD1-mediated immunity, polarized cytokine response, altered adhesion and increased intracellular protein transport and processing of leukemic cells. Leukemia 16, 2429-2437

Stanford University, Palo Alto, California, United States
Leukemia (Impact Factor: 10.43). 01/2003; 16(12):2429-37. DOI: 10.1038/sj.leu.2402711
Source: PubMed


We used oligonucleotide microarrays to profile the expression of chronic lymphocytic leukemia (CLL) B cells from eight patients compared with CD5-expressing normal B cells from four donors and with pooled normal circulating B cells. Of 6790 genes examined, we identified 87 genes that were differentially expressed at least two-fold between CLL and the normal B cells. CLL cells significantly down-regulated transcripts from CD1c and CD1d genes, which encode proteins known to present lipid antigen and mediate innate and adaptive immunity. The expression pattern was also consistent with reduced signaling by interferon gamma but increased response to interleukin 4 in leukemic cells. CLL cells increased the expression of several collagen-associated extracellular matrix and adhesion molecules, up-regulated many genes involved in intracellular protein transport and processing, while downregulating genes involved in proliferation and metabolism. Based on the expression pattern, we propose that CLL-B cells prolong their survival through increased interaction with survival factors such as IL-4, and through various mechanisms of evading the immune response, such as turning off the expression of CD1c and CD1d, reducing immunogenic response to interferon gamma, inactivating T cell in B-T interaction and increasing the expression of immunoglobulin receptors which neutralize antibody-dependent cell-mediated cytotoxicity.

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    • "However, sets of 54 and 11 genes with differential responses (most of them specific) were found in CLL and NBC, respectively. Previous studies had reported increased expression of the IL-4 receptor in CLL, at the protein [13], and the mRNA level by microarray [5], but in another study differences were not found [36]. In our study, as in the latter, no significant differences were observed between the basal levels of IL4R mRNA in CLL and NBC. "
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    ABSTRACT: Interleukin 4 (IL-4), an essential mediator of B cell development, plays a role in survival of chronic lymphocytic leukemia (CLL) cells. To obtain new insights into the function of the IL-4 pathway in CLL, we analyzed the gene expression response to IL-4 in CLL and in normal B cells (NBC) by oligonucleotide microarrays, resulting in the identification of 232 non-redundant entities in CLL and 146 in NBC (95 common, 283 altogether), of which 189 were well-defined genes in CLL and 123 in NBC (83 common, 229 altogether) (p<0.05, 2-fold cut-off). To the best of our knowledge, most of them were novel IL-4 targets for CLL (98%), B cells of any source (83%), or any cell type (70%). Responses were significantly higher for 54 and 11 genes in CLL and NBC compared to each other, respectively. In CLL, ZAP-70 status had an impact on IL-4 response, since different sets of IL-4 targets correlated positively or negatively with baseline expression of ZAP-70. In addition, the NFκB inhibitor 6-Amino-4-(4-phenoxyphenethylamino)quinazoline, which reversed the anti-apoptotic effect of IL-4, preferentially blocked the response of genes positively correlated with ZAP-70 (e.g. CCR2, SUSD2), but enhanced the response of genes negatively correlated with ZAP-70 (e.g. AUH, BCL6, LY75, NFIL3). Dissection of the gene expression response to IL-4 in CLL and NBC contributes to the understanding of the anti-apoptotic response. Initial evidence of a connection between ZAP-70 and NFκB supports further exploration of targeting NFκB in the context of the assessment of inhibition of the IL-4 pathway as a therapeutic strategy in CLL, especially in patients expressing bad prognostic markers.
    Full-text · Article · Oct 2014 · PLoS ONE
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    • "Although XLP patients typically develop EBV-associated non Hodgkin B cell lymphomas [45], recent studies suggest that T cells restricted to non-classical MHC Class-I molecules are important for immune surveillance of hematological malignancies [46]. In particular, iNKT cells, that are CD1d-restricted cells, can induce cell death of chronic lymphocytic leukemia cells after stimulation with alphaGalCer [47], and can trigger secondary anti-lymphoma response in murine models of lymphoma [48]. Significantly, CD1d is expressed by neoplastic cells of HL and iNKT cells have been detected in cell suspensions of HL clinical samples [46]. "
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    ABSTRACT: Hermansky Pudlak type 2 syndrome (HPS2) is a rare autosomal recessive primary immune deficiency caused by mutations on β3A gene (AP3B1 gene). The defect results in the impairment of the adaptor protein 3 (AP-3) complex, responsible for protein sorting to secretory lysosomes leading to oculo-cutaneous albinism, bleeding disorders and immunodeficiency. We have studied peripheral blood and lymph node biopsies from two siblings affected by HPS2. Lymph node histology showed a nodular lymphocyte predominance type Hodgkin lymphoma (NLPHL) in both HPS2 siblings. By immunohistochemistry, CD8 T-cells from HPS2 NLPHL contained an increased amount of perforin (Prf) + suggesting a defect in the release of this granules-associated protein. By analyzing peripheral blood immune cells we found a significant reduction of circulating NKT cells and of CD56(bright)CD16(-) Natural Killer (NK) cells subset. Functionally, NK cells were defective in their cytotoxic activity against tumor cell lines including Hodgkin Lymphoma as well as in IFN-γ production. This defect was associated with increased baseline level of CD107a and CD63 at the surface level of unstimulated and IL-2-activated NK cells. In summary, these results suggest that a combined and profound defect of innate and adaptive effector cells might explain the susceptibility to infections and lymphoma in these HPS2 patients.
    Full-text · Article · Nov 2013 · PLoS ONE
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    ABSTRACT: Speechreading increases intelligibility in human speech perception. This suggests that conventional acoustic-based speech processing can benefit from the addition of visual information. This paper exploits speechreading for joint audio-visual speech recognition. We first present a color-based feature extraction algorithm that is able to extract salient visual speech features reliably from a frontal view of the talker in a video sequence. Then, a new fusion strategy using a coupled hidden Markov model (CHMM) is proposed to incorporate visual modality into the acoustic subsystem. By maintaining temporal coupling across the two modalities at the feature level and allowing asynchrony in the state at the same time, a CHMM provides a better model for capturing temporal correlations between the two streams of information. The experimental results demonstrate that the combined audio-visual system outperforms the acoustic-only recognizer over a wide range of noise levels.
    Preview · Conference Paper · Feb 2002
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