title: Novel and highly recurrent chromosomal alterations in Sézary syndrome.
abstract: 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, cMYC-regulating proteins, mediators of MYC-induced apoptosis, and IL-2 signaling pathway components.
authors.affiliation: Department of Dermatology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Maarten H
authors.initials: MH
authors.lastname: Vermeer
authors.forename: Remco
authors.initials: R
authors.lastname: van Doorn
authors.forename: Remco
authors.initials: R
authors.lastname: Dijkman
authors.forename: Xin
authors.initials: X
authors.lastname: Mao
authors.forename: Sean
authors.initials: S
authors.lastname: Whittaker
authors.forename: Pieter C
authors.initials: PC
authors.lastname: van Voorst Vader
authors.forename: Marie-Jeanne P
authors.initials: MJ
authors.lastname: Gerritsen
authors.forename: Marie-Louise
authors.initials: ML
authors.lastname: Geerts
authors.forename: Sylke
authors.initials: S
authors.lastname: Gellrich
authors.forename: Ola
authors.initials: O
authors.lastname: Söderberg
authors.forename: Karl-Johan
authors.initials: KJ
authors.lastname: Leuchowius
authors.forename: Ulf
authors.initials: U
authors.lastname: Landegren
authors.forename: Jacoba J
authors.initials: JJ
authors.lastname: Out-Luiting
authors.forename: Jeroen
authors.initials: J
authors.lastname: Knijnenburg
authors.forename: Marije
authors.initials: M
authors.lastname: Ijszenga
authors.forename: Karoly
authors.initials: K
authors.lastname: Szuhai
authors.forename: Rein
authors.initials: R
authors.lastname: Willemze
authors.forename: Cornelis P
authors.initials: CP
authors.lastname: Tensen
mesh_terms: D000368:Aged; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D002869:Chromosome Aberrations; D004273:DNA, Neoplasm / Q000097:blood / Q000235:genetics; D005260:Female; D006801:Humans; D008297:Male; D009693:Nucleic Acid Hybridization; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D012751:Sezary Syndrome / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D012878:Skin Neoplasms / Q000235:genetics* / Q000276:immunology / Q000473:pathology
chemical_list: D004273:DNA, Neoplasm