Uncovering the potential of PI3K inhibitors in cutaneous T cell lymphoma: insights from high throughput in vitro screenings

2021 ◽  
Author(s):  
Amber Loren O. King ◽  
Fatima N. Mirza ◽  
Julia M. Lewis ◽  
Shiela Umlauf ◽  
Yulia Surosteva ◽  
...  
Keyword(s):  
T Cell ◽  
High Throughput ◽  
Cell Lymphoma ◽  
T Cell Lymphoma ◽  
Cutaneous T Cell Lymphoma ◽  
Pi3k Inhibitors

Biomarkers of Vorinostat Resistance in Cutaneous T-Cell Lymphoma.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1381-1381
Author(s):  
Chunlei Zhang ◽  
Baoqiang Li ◽  
Rakhshandra Talpur ◽  
C. Cameron Yin ◽  
Madeleine Duvic
Keyword(s):  
Gene Expression ◽  
T Cell ◽  
Mononuclear Cells ◽  
Cell Lymphoma ◽  
T Cell Lymphoma ◽  
Differentially Expressed ◽  
Cytokine Signaling ◽  
Cutaneous T Cell Lymphoma ◽  
Phase Ii Studies

Abstract Profiling gene expression with DNA microarray technology has elucidated novel therapeutic targets and led the approval of a number of targeted therapeutic agents for the treatment of cancer. Vorinostat (suberoylanilide hydroxamic acid, SAHA) is a pan-histone deacetylase (HDAC) inhibitor that has demonstrated an overall response rate of approximately 24–30% in two phase II studies of cutaneous T cell lymphoma (CTCL) patients. There are currently no known specific biomarkers to indicate resistance to vorinostat. To identify genes resistant to vorinostat we compared profiles using the Aligent whole human genome oligo microarrays containing ∼41,000 genes/transcripts in vitro in vorinostat-resistant MJ and -sensitive HH CTCL cell lines treated with 1 μM of vorinostat for 24 hours and compared them to patients’ peripheral blood mononuclear cells (PBMCs) before and during oral therapy. There were 3151 (7.7%) genes/transcripts differentially expressed in vitro in treated resistant MJ cells compared to untreated vehicle control (p < 0.001). We also studied differential gene expression in two clinically resistant Sézary patients’ PBMCs taken at baseline and four weeks after oral vorinostat (400 mg daily or 300 mg bid 3 days/wk). In patients’ PBMCs, 585 (1.4%) and 2744 (6.7%) differentially expressed genes/transcripts (p < 0.001) were identified, respectively. Genes that were up-regulated both in vitro and in vivo included a tumor necrosis factor receptor super-family member 11a (TNFRSF11a or RANK), matrix metallopeptidase 9 (MMP9), suppressor of cytokine signaling 3 (SOCS3), vinculin (VCL) and KIAA1840. Genes that were down-regulated in both included adenylate kinase 3-like 1 (AK3L1), leucine rich repeat and fibronectin type III domain containing 4 (LRFN4), and AL359650. Increased RANK, MMP9 and SOCS3 mRNA expression in MJ compared to HH cells and in three resistant versus three vorinostat responding Sézary patients’ PBMCs was confirmed using quantitative real-time PCR. In conclusion, our results suggest that oligonucleotide microarray analysis may identify biomarkers of resistance to vorinostat which would be helpful to select patients who may not benefit from treatment. These findings provide the rationale for future functional studies and development of more effective use of HDAC inhibitors for CTCL patients.

scholarly journals Selective inhibition of HDAC6 sensitizes cutaneous T‑cell lymphoma to PI3K inhibitors

2020 ◽  
Vol 20 (1) ◽  
pp. 533-540
Author(s):  
Malgorzata Bobrowicz ◽  
Aleksander Slusarczyk ◽  
Joanna Domagala ◽  
Michal Dwojak ◽  
Desislava Ignatova ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Lymphoma ◽  
Selective Inhibition ◽  
T Cell Lymphoma ◽  
Cutaneous T Cell Lymphoma ◽  
Pi3k Inhibitors

The growth of cutaneous T-cell lymphoma is stimulated by immature dendritic cells

Blood ◽  
2002 ◽  
Vol 99 (8) ◽  
pp. 2929-2939 ◽  
Author(s):  
Carole L. Berger ◽  
Douglas Hanlon ◽  
Daniel Kanada ◽  
Madhav Dhodapkar ◽  
Vivian Lombillo ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Biology ◽  
Cell Lymphoma ◽  
Close Association ◽  
Clinical Intervention ◽  
Cell Receptor ◽  
T Cell Lymphoma ◽  
Cutaneous T Cell Lymphoma

Abstract In the initial stage of cutaneous T-cell lymphoma (CTCL), proliferating CTCL cells are concentrated in the epidermis in close association with an immature dendritic cell (DC), the Langerhans cell. Because long-term in vitro culture of CTCL cells has proven difficult, the in vivo association with the major antigen-presenting cell (APC) of the epidermis has been postulated to play a role in directly stimulating the clonal T-cell proliferation. We report that CTCL cells can be reproducibly grown in culture for 3 months when cocultured with immature DCs. CTCL cells retain the phenotype and genotype of the initial malignant clone, whereas the APCs are a mixture of immature and mature DCs. CTCL cell and DC survival was dependent on direct membrane contact. Growth was inhibited by antibodies that bound to the T-cell receptor (TCR) or interfered with the interaction of CD40 with its ligand on the CTCL cell. Addition of antibody to CD3 or the clonotypic TCR caused rapid CTCL cell apoptosis followed by engulfment by avidly phagocytic immature DCs and subsequent DC maturation. The opportunity to study CTCL cells and immature DCs for prolonged periods will facilitate studies of tumor cell biology and will allow investigation of the intriguing hypothesis that CTCL cell growth is driven through TCR recognition of class II–presented self-peptides. In addition, the culture of CTCL cells will permit evaluation of therapies in vitro before clinical intervention, thereby improving safety and efficacy.

Cutaneous T-cell lymphoma: malignant proliferation of T-regulatory cells

Blood ◽  
2005 ◽  
Vol 105 (4) ◽  
pp. 1640-1647 ◽  
Author(s):  
Carole L. Berger ◽  
Robert Tigelaar ◽  
Justine Cohen ◽  
Kavita Mariwalla ◽  
Jennifer Trinh ◽  
...  
Keyword(s):  
T Cell ◽  
Transforming Growth Factor ◽  
Cell Lymphoma ◽  
Interleukin 10 ◽  
T Cell Lymphoma ◽  
Cutaneous T Cell Lymphoma ◽  
Membrane Expression ◽  
Cell Conversion ◽  
Treg Phenotype

Abstract Studies in an in vitro model of cutaneous T-cell lymphoma (CTCL) demonstrated that CTCL cell proliferation is stimulated by direct contact with autologous, immature dendritic cells (DCs), suggesting that CD4+ CTCL cell division is driven by antigens presented by DC major histocompatibility complex (MHC) class 2. We now report that the T-cell receptor (TCR) of the CD4+ CTCL cells is triggered after interaction with DCs loaded with apoptotic CTCL cells, as shown by reduced membrane expression of CD3 and the TCR, up-regulation of cytotoxic T lymphocyte antigen-4 (CTLA-4), and calcium mobilization. CTCL cells adopt a T-regulatory (Treg) phenotype expressing CD25/CTLA-4 and FoxP3 and secreting interleukin-10 (IL-10) and transforming growth factor-β (TGF-β). Treg CTCL cells suppress normal T-cell antigen-driven secretion of IL-2 and interferon-γ (IFN-γ). Blocking DC MHC class 2 expression or transport inhibited CTCL cell adoption of a Treg phenotype. Allogeneic CTCL cells or normal CD4 T cells served as sources of apoptotic material for CTCL cell conversion to a Treg phenotype. Conversion of CTCL cells to Treg cells may explain the anergic, immunosuppressive nature of the malignancy. (Blood. 2005;105:1640-1647)

scholarly journals JAK3 Is Expressed in the Nucleus of Malignant T Cells in Cutaneous T Cell Lymphoma (CTCL)

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 280
Author(s):  
Chella Krishna Vadivel ◽  
Maria Gluud ◽  
Sara Torres-Rusillo ◽  
Lasse Boding ◽  
Andreas Willerslev-Olsen ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Rna Polymerase Ii ◽  
Nuclear Localization ◽  
Nuclear Export ◽  
Cell Lymphoma ◽  
T Cell Lymphoma ◽  
Cutaneous T Cell Lymphoma ◽  
Malignant T Cells

Perturbation in JAK-STAT signaling has been reported in the pathogenesis of cutaneous T cell lymphoma (CTCL). JAK3 is predominantly associated with the intra-cytoplasmic part of IL-2Rγc located in the plasma membrane of hematopoietic cells. Here we demonstrate that JAK3 is also ectopically expressed in the nucleus of malignant T cells. We detected nuclear JAK3 in various CTCL cell lines and primary malignant T cells from patients with Sézary syndrome, a leukemic variant of CTCL. Nuclear localization of JAK3 was independent of its kinase activity whereas STAT3 had a modest effect on nuclear JAK3 expression. Moreover, JAK3 nuclear localization was only weakly affected by blockage of nuclear export. An inhibitor of the nuclear export protein CRM1, Leptomycin B, induced an increased expression of SOCS3 in the nucleus, but only a weak increase in nuclear JAK3. Importantly, immunoprecipitation experiments indicated that JAK3 interacts with the nuclear protein POLR2A, the catalytic subunit of RNA Polymerase II. Kinase assays showed tyrosine phosphorylation of recombinant human Histone H3 by JAK3 in vitro—an effect which was blocked by the JAK inhibitor (Tofacitinib citrate). In conclusion, we provide the first evidence of nuclear localization of JAK3 in malignant T cells. Our findings suggest that JAK3 may have a cytokine-receptor independent function in the nucleus of malignant T cells, and thus a novel non-canonical role in CTCL.

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