Primary Cutaneous T-Cell Lymphomas Show a Deletion or Translocation Affecting <i>NAV3</i>, the Human <i>UNC-53</i> Homologue

Karenko, Leena; Hahtola, Sonja; Päivinen, Suvi; Karhu, Ritva; Syrjä, Sanna; Kähkönen, Marketta; Nedoszytko, Bogusław; Kytölä, Soili; Zhou, Ying; Blazevic, Vesna; Pesonen, Maria; Nevala, Hanna; Nupponen, Nina N.; Sihto, Harri; Krebs, Inge; Poustka, Annemarie; Roszkiewicz, Jadwiga; Saksela, Kalle; Peterson, Pärt; Visakorpi, Tapio; Ranki, Annamari

doi:10.1158/0008-5472.can-04-0366

Cited by 96 publications

(83 citation statements)

References 57 publications

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“…Previously, several studies on CTCL have pointed out chromosomal instability as a hallmark of the disease (10,39,43); thus, chromosomal aberrations may affect gene expression (11). The DLG5 tumor suppressor gene, down-regulated in our Sezary syndrome samples, is located in 10q23, a chromosomal area often deleted in CTCL (10,40).…”

Section: Discussionmentioning

confidence: 81%

“…Additionally, 4q and 12q also contain down-regulated genes and deleted areas. We have observed previously gains of chromosome arms 1q, 3p, 3q, 4q, and 16q by CGH in CTCL, 6 and diverse aberrations of these chromosomes are common by other cytogenetic or molecular cytogenetic methods (11,40,43). Thus, the above chromosome arms are potential targets for searching for further recurrent gene aberrations in CTCL.…”

Section: Discussionmentioning

confidence: 85%

“…As an internal control, normal male and female DNA were cohybridized and only differences in sex chromosomes were identified. Multifluor fluorescent in situ hybridization of metaphase preparations from cases 1 to 3, 5, 7, and 8 was done as described previously (11). At least 50 metaphases were analyzed for each case.…”

Section: Methodsmentioning

confidence: 99%

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Th1 Response and Cytotoxicity Genes Are Down-Regulated in Cutaneous T-Cell Lymphoma

Hahtola

Tuomela

Elo

et al. 2006

Clinical Cancer Research

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Purpose: Increased production of Th2 cytokines characterizes Sezary syndrome, the leukemic form of cutaneous T-cell lymphomas (CTCL). To identify the molecular background and to study whether shared by the most common CTCL subtype, mycosis fungoides, we analyzed the gene expression profiles in both subtypes. Experimental Design: Freshly isolated cells from 30 samples, representing skin, blood, and enriched CD4+ cell populations of mycosis fungoides and Sezary syndrome, were analyzed with Affymetrix (Santa Clara, CA) oligonucleotide microarrays, quantitative PCR, or immunohistochemistry. The gene expression profiles were combined with findings of comparative genomic hybridization of the same samples to identify chromosomal changes affecting the aberrant gene expression. Results: We identified a set of Th1-specific genes [e.g., TBX21 (T-bet), NKG7, and SCYA5 (RANTES)] to be down-regulated in Sezary syndrome as well as in a proportion of mycosis fungoides samples. In both Sezary syndrome and mycosis fungoides blood samples, the S100P and LIR9 gene expression was up-regulated. In lesional skin, IL7R and CD52 were up-regulated. Integration of comparative genomic hybridization and transcriptomic data identified chromosome arms 1q, 3p, 3q, 4q, 12q, 16p, and 16q as likely targets for new CTCL-associated gene aberrations. Conclusions: Our findings revealed several new genes involved in CTCL pathogenesis and potential therapeutic targets. Down-regulation of a set of genes involved in Th1 polarization, including the major Th1-polarizing factor, TBX21, was for the first time associated with CTCL. In addition, a plausible explanation for the proliferative response of CTCL cells to locally produced interleukin-7 was revealed.

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Section: Discussionmentioning

confidence: 81%

Section: Discussionmentioning

confidence: 85%

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Th1 Response and Cytotoxicity Genes Are Down-Regulated in Cutaneous T-Cell Lymphoma

Hahtola

Tuomela

Elo

et al. 2006

Clinical Cancer Research

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“…Haploinsufficiency of some tumor suppressor genes have been described in MF/SS, including p15, p16, 48 and NAV3. 49 In contrast to tumor suppressors that act in the cytosol to regulate cell growth and survival, C2GnT-I is an enzyme that acts in the Golgi to modify glycoproteins destined for export to the cell surface, where glycoproteins interact with the extracellular milieu. Protein glycosylation is a complex process that is affected by glycosyltransferase abundance and activity, glycosyltransferase localization within the Golgi, and rate of glycoprotein transport through the Golgi.…”

Section: Discussionmentioning

confidence: 99%

Haploinsufficiency of C2GnT-I glycosyltransferase renders T lymphoma cells resistant to cell death

Cabrera

Amano

Mitoma

et al. 2006

Blood

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Neoplastic T cells in mycosis fungoides (MF)are resistant to apoptotic agents, including galectin-1 that is abundant in skin. Although MF cells are typically CD7 ؊ , and thus galectin-1 resistant, CD7 ؉ HH cells, derived from a patient with MF, were also resistant to galectin-1. HH cells demonstrate altered cell surface glycosylation, with loss of core 2 Oglycan ligands for galectin-1 created by core 2 ␤1,6-N-acetylglucosaminyltransferase (C2GnT-I). Loss of core 2 O-glycans on tumor cells was also seen in primary CD7 ؉ MF lesions. Surprisingly, HH cells are heterozygous for a C2GnT-I point mutation, yet this mutation resulted in a dramatic reduction in cellular glycosyltransferase activity. Expression of wild-type C2GnT-I in human HH cells, or murine lymphoma cells that lack C2GnT-I, restored core 2 O-glycan expression and susceptibility to galectin-1, whereas mutant enzyme lacked activity and did not restore core 2 O-glycan expression or susceptibility to galectin-1. Mutant enzyme did not have a dominant negative effect by affecting dimerization or activity of wild-type enzyme; rather, C2GnT-I haploinsufficiency is sufficient for loss of core 2 O-glycan expression and galectin-1 resistance. Thus, glycosyltransferase haploinsufficiency results in altered cellular glycosylation and resistance to cell death, identifying a new survival mechanism for T-lymphoma cells.

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“…Cytogenetic and conventional comparative genomic hybridization (CGH) studies have uncovered a number of structural and numerical chromosomal aberrations in Sz, but highly recurrent genetic lesions have not been identified (2)(3)(4)(5)(6)(7). Gene expression profiling of Sézary cells has revealed deregulated expression of several oncogenes and tumor suppressor genes, including TGF-b receptor II, JUNB, STAT4, MMP9, MXI1, and TWIST (8)(9)(10)(11).…”

Section: Introductionmentioning

confidence: 99%

Novel and Highly Recurrent Chromosomal Alterations in Sézary Syndrome

Vermeer¹,

Doorn²,

Dijkman³

et al. 2008

Cancer Research

177

187

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This study was designed to identify highly recurrent genetic alterations typical of Sézary syndrome (Sz), an aggressive cutaneous T-cell lymphoma/leukemia, possibly revealing pathogenetic mechanisms and novel therapeutic targets. High-resolution array-based comparative genomic hybridization was done on malignant T cells from 20 patients. Expression levels of selected biologically relevant genes residing within loci with frequent copy number alteration were measured using quantitative PCR. Combined binary ratio labeling-fluorescence in situ hybridization karyotyping was done on malignant cells from five patients. Minimal common regions with copy number alteration occurring in at least 35% of patients harbored 15 bona fide oncogenes and 3 tumor suppressor genes. Based on the function of the identified oncogenes and tumor suppressor genes, at least three molecular mechanisms are relevant in the pathogenesis of Sz. First, gain of cMYC and loss of cMYC antagonists (MXI1 and MNT) were observed in 75% and 40% to 55% of patients, respectively, which were frequently associated with deregulated gene expression. The presence of cMYC/ MAX protein heterodimers in Sézary cells was confirmed using a proximity ligation assay. Second, a region containing TP53 and genome maintenance genes (RPA1/HIC1) was lost in the majority of patients. Third, the interleukin 2 (IL-2) pathway was affected by gain of STAT3/STAT5 and IL-2 (receptor) genes in 75% and 30%, respectively, and loss of TCF8 and DUSP5 in at least 45% of patients. In sum, the Sz genome is characterized by gross chromosomal instability with highly recurrent gains and losses. Prominent among deregulated genes are those encoding cMYC, cMYCregulating proteins, mediators of MYC-induced apoptosis, and IL-2 signaling pathway components. [Cancer Res 2008; 68(8):2689-98]

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Primary Cutaneous T-Cell Lymphomas Show a Deletion or Translocation Affecting NAV3, the Human UNC-53 Homologue

Cited by 96 publications

References 57 publications

Th1 Response and Cytotoxicity Genes Are Down-Regulated in Cutaneous T-Cell Lymphoma

Th1 Response and Cytotoxicity Genes Are Down-Regulated in Cutaneous T-Cell Lymphoma

Haploinsufficiency of C2GnT-I glycosyltransferase renders T lymphoma cells resistant to cell death

Novel and Highly Recurrent Chromosomal Alterations in Sézary Syndrome

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