Regulation of CD38 in proliferating chronic lymphocytic leukemia cells stimulated with CD154 and interleukin-4

Willimott, Shaun; Baou, Maria; Huf, Sarah; Deaglio, Silvia; Wagner, Simon D.

doi:10.3324/haematol.11340

Cited by 21 publications

(19 citation statements)

References 44 publications

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“…The CD40L-expressing fibroblast stromal cell system has made it possible to isolate the epigenetic changes that occur in CLL upon treatment with such inhibitors (36)(37)(38). Furthermore, this being the first murine-based feeder cell system provides an obvious advantage when using PCR specific for a rare-expressed human gene.…”

Section: Discussionmentioning

confidence: 99%

Treatment of Chronic Lymphocytic Leukemia with a Hypomethylating Agent Induces Expression of NXF2, an Immunogenic Cancer Testis Antigen

Dubovsky

McNeel

Powers

et al. 2009

Clinical Cancer Research

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Purpose: Critical to the success of active immunotherapy against cancer is the identification of immunologically recognized cancer-specific proteins with low tolerogenic potential. Cancer testis antigens (CTA), in particular, fulfill this requirement as a result of their aberrant expression restricted to cancer cells and lack of expression in normal tissues bypassing tolerogenic mechanisms against self. Although CTAs have been extensively studied in solid malignancies, little is known regarding their expression in chronic lymphocytic leukemia (CLL). Experimental Design: Using a two-pronged approach we evaluated the immunogenicity of 29 CTAs in 22 patients with CLL and correlated these results to reverse transcriptase PCR data from CLL cell lines and patient cells. Results: We identified IgG-specific antibodies for one antigen, NXF2, and confirmed this response by ELISA and Western blot. We found that treatment of CLL with 5-aza-2′-deoxycytidine can induce expression of NXF2 that lasted for several weeks after treatment. Treatment also increased levels of MHC and costimulatory molecules (CD80, CD86, and CD40) necessary for antigen presentation. In addition, we identified other promising antigens that may have potential immunotherapeutic application. Conclusions: Our findings suggest that NXF2 could be further pursued as an immunotherapeutic target in CLL, and that treatment with demethylating agents could be exploited to specifically modulate CTA expression and effective antigen presentation in malignant B cells.

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Section: Discussionmentioning

confidence: 99%

Treatment of Chronic Lymphocytic Leukemia with a Hypomethylating Agent Induces Expression of NXF2, an Immunogenic Cancer Testis Antigen

Dubovsky

McNeel

Powers

et al. 2009

Clinical Cancer Research

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“…[43][44][45][46][47] Venetoclax (10 nM) induced cytotoxicity was significantly decreased in both coculture systems, with an average cell kill of 8% (n 5 6) for CD40L-cocultured cells and 30% (n 5 4) for OP9-cocultured cells compared with 60% kill in unstimulated (suspension) CLL cells (n 5 6) ( Figure 5A, bottom left panel and B; supplemental Figure 4A). In unstimulated cells, the high total kill (.95%) measured for the drug combination can be attributed to the single-agent effect of venetoclax (supplemental Figure 4A, bottom panel).…”

Section: -41mentioning

confidence: 99%

High-content screening identifies kinase inhibitors that overcome venetoclax resistance in activated CLL cells

Oppermann

Ylanko

Shi

et al. 2016

Blood

105

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“…20,56 Therefore, it is a "real-time" indicator of the level of leukemic proliferation and thereby actual or potential clonal evolution, which ultimately determines the clinical course and outcome for an individual patient. This evolutionary change can be affected by many parameters 84 ; in particular, it can be influenced by stimulation through cell surface receptors for antigens, 83 cytokines, chemokines, 19,74,82 etc, within the microenvironment. Simplistically viewed, the more CD38 ϩ cells in a clone, the greater the number of dividing cells and hence the greater the chance for occurrence of new DNA lesions, enhanced clonal aggressiveness, and worse clinical outcome.…”

Section: Pros and Cons In Using Cd38 As A Marker And A Therapeutic Tamentioning

confidence: 99%

“…24 Besides being variable among CLL patients, CD38 expression can change at anatomic sites, being higher in BM and in areas of intense CLL/T lymphocyte contact. 19 Accordingly, during CLL cell activation in vitro, CD38 expression can be up-regulated by a number of different signals, such as IL-2, 74 CD40L plus IL-4, 82 CpG oligonucleotides, 83 and coculture with mesenchymal stem cells. 84 A single nucleotide polymorphism (C Ͼ G, rs6449182) is located at the 5Ј end of intron 1 of CD38, 81 and allelic frequencies of the polymorphism in healthy Italian, Spanish, Irish, and Polish populations have been defined.…”

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confidence: 99%

CD38 and chronic lymphocytic leukemia: a decade later

Malavasi

Deaglio

Damle

et al. 2011

Blood

196

160

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This review highlights a decade of investigations into the role of CD38 in CLL. CD38 is accepted as a dependable marker of unfavorable prognosis and as an indicator of activation and proliferation of cells when tested. Leukemic clones with higher numbers of CD38 ؉ cells are more responsive to BCR signaling and are characterized by enhanced migration. In vitro activation through CD38 drives CLL proliferation and chemotaxis via a signaling pathway that includes ZAP-70 and ERK1/2. Finally, CD38 is under a polymorphic transcriptional control after external signals.Consequently, CD38 appears to be a global molecular bridge to the environment, promoting survival/proliferation over apoptosis. Together, this evidence contributes to the current view of CLL as a chronic disease in which the host's microenvironment promotes leukemic cell growth and also controls the sequential acquisition and accumulation of genetic alterations. This view relies on the existence of a set of surface molecules, including CD38, which support proliferation and survival of B cells on their way to and after neoplastic transformation. The second decade of studies on CD38 in CLL will tell if the molecule is an effective target for antibody-mediated therapy in this currently incurable leukemia. (Blood. 2011;118(13):3470-3478)The current view of chronic lymphocytic leukemia (CLL) is that of a disease characterized by a dynamic balance between cells circulating in the blood and cells located in permissive niches in lymphoid organs. 1 The former are primarily mature-looking small lymphocytes resistant to apoptosis, whereas the latter are composed of lymphocytes that undergo either proliferation or apoptosis according to the environment. 2 The heterogeneous clinical outcome of CLL patients is dictated, at least in part, by the nature of these microenvironmental signals and interactions that can promote or impair accumulation of genomic alterations. 3 Detailed immunophenotypic and genetic analyses of different neoplastic clones have led to the identification of a number of molecular markers, some of which are gaining relevance in clinical practice to predict disease outcome. [4][5][6][7] Cell surface CD38 is one of these markers.This review highlights a decade of investigations into the role of CD38 in CLL. An association between CD38 expression by CLL cells and a more aggressive clinical behavior was first reported in 1999 4 and confirmed by several subsequent studies. [8][9][10][11][12] Consequently, determination of the percentage of CD38-expressing cells within a clone has become part of the workup of CLL patients in many clinical centers, 13 and it is generally accepted that CD38 ϩ patients will have a shorter progression-free interval, require earlier and more frequent treatments, and ultimately die sooner. 4 The underlying question behind these clinical observations is why expression of this molecule on the cell surface would correlate with a worse clinical outcome. The most obvious possibility is that CD38 expression reflects events occurring in...

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Regulation of CD38 in proliferating chronic lymphocytic leukemia cells stimulated with CD154 and interleukin-4

Cited by 21 publications

References 44 publications

Treatment of Chronic Lymphocytic Leukemia with a Hypomethylating Agent Induces Expression of NXF2, an Immunogenic Cancer Testis Antigen

Treatment of Chronic Lymphocytic Leukemia with a Hypomethylating Agent Induces Expression of NXF2, an Immunogenic Cancer Testis Antigen

High-content screening identifies kinase inhibitors that overcome venetoclax resistance in activated CLL cells

CD38 and chronic lymphocytic leukemia: a decade later

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