title: Genomic alterations of the JAK2 and PDL loci occur in a broad spectrum of lymphoid malignancies.
abstract: The recurrent 9p24.1 aberrations in lymphoid malignancies potentially involving four cancer-related and druggable genes (JAK2, CD274/PDL1, PDCD1LG2/PDL2, and KDM4C/JMJD2Cl) are incompletely characterized. To gain more insight into the anatomy of these abnormalities, at first we studied 9p24.1 alterations in 18 leukemia/lymphoma cases using cytogenetic and molecular techniques. The aberrations comprised structural (nine cases) and numerical (nine cases) alterations. The former lesions were heterogeneous but shared a common breakpoint region of 200 kb downstream of JAK2. The rearrangements predominantly targeted the PDL locus. We have identified five potential partner genes of PDL1/2: PHACTR4 (1p34), N4BP2 (4p14), EEF1A1 (6q13), JAK2 (9p24.1), and IGL (22q11). Interestingly, the cryptic JAK2-PDL1 rearrangement was generated by a microdeletion spanning the 3'JAK2-5'PDL1 region. JAK2 was additionally involved in a cytogenetically cryptic IGH-mediated t(9;14)(p24.1;q32) found in two patients. This rare but likely underestimated rearrangement highlights the essential role of JAK2 in B-cell neoplasms. Cases with amplification of 9p24.1 were diagnosed as primary mediastinal B-cell lymphoma (five cases) and T-cell lymphoma (four cases). The smallest amplified 9p24.1 region was restricted to the JAK2-PDL1/2-RANBP6 interval. In the next step, we screened 200 cases of classical Hodgkin lymphoma by interphase FISH and identified PDL1/2 rearrangement (CIITA- and IGH-negative) in four cases (2%), what is a novel finding. Forty (25%) cases revealed high level amplification of 9p24.1, including four cases with a selective amplification of PDL1/2. Altogether, the majority of 9p24.1 rearrangements occurring in lymphoid malignancies seem to target the programmed death-1 ligands, what potentiates the therapeutic activity of PD-1 blockade in these tumors. © 2016 Wiley Periodicals, Inc.
authors: Center for Human Genetics, KU Leuven, Leuven, Belgium.|Center for the Biology of Disease, VIB, Leuven, Belgium.
authors: Katrien
authors: K
authors: Van Roosbroeck
authors: Center for Human Genetics, KU Leuven, Leuven, Belgium.
authors: Julio Finalet
authors: JF
authors: Ferreiro
authors: Department of Pathology UZ Leuven, Translational Cell and Tissue Research, K.U. Leuven, Leuven, Belgium.
authors: Thomas
authors: T
authors: Tousseyn
authors: Center for Human Genetics, KU Leuven, Leuven, Belgium.
authors: Jo-Anne
authors: JA
authors: van der Krogt
authors: Center for Human Genetics, KU Leuven, Leuven, Belgium.
authors: Lucienne
authors: L
authors: Michaux
authors: Department of Pathology and Laboratory Diagnostic, Maria Sklodowska-Curie Memorial Cancer Centre and Institute, Warsaw, Poland.
authors: Barbara
authors: B
authors: Pienkowska-Grela
authors: Department of Pathology, Cliniques Universitaires Saint-Luc, Université Catholique De Louvain, Brussels, Belgium.
authors: Ivan
authors: I
authors: Theate
authors: Department of Pathology, AZ St Jan AV, Brugge, Belgium.
authors: Pascale
authors: P
authors: De Paepe
authors: Department of Hematology, UZ Leuven, Leuven, Belgium.
authors: Daan
authors: D
authors: Dierickx
authors: Department of Hematology, Mont-Godinne University Hospital, Yvoir, Belgium.
authors: Chantal
authors: C
authors: Doyen
authors: Center for Human Genetics, KU Leuven, Leuven, Belgium.
authors: Natalie
authors: N
authors: Put
authors: Center for Human Genetics, KU Leuven, Leuven, Belgium.|Center for the Biology of Disease, VIB, Leuven, Belgium.
authors: Jan
authors: J
authors: Cools
authors: Center for Human Genetics, KU Leuven, Leuven, Belgium.
authors: Peter
authors: P
authors: Vandenberghe
authors: Center for Human Genetics, KU Leuven, Leuven, Belgium.
authors: Iwona
authors: I
authors: Wlodarska
mesh_terms: D060890:B7-H1 Antigen / Q000235:genetics*; D002871:Chromosome Banding; D020869:Gene Expression Profiling; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics*; D007621:Karyotyping; D008223:Lymphoma / Q000235:genetics*; D009154:Mutation
chemical_list: D060890:B7-H1 Antigen; C423236:CD274 protein, human; C507924:JAK2 protein, human; D053614:Janus Kinase 2