title: Integrative analysis reveals selective 9p24.1 amplification, increased PD-1 ligand expression, and further induction via JAK2 in nodular sclerosing Hodgkin lymphoma and primary mediastinal large B-cell lymphoma.
abstract: Classical Hodgkin lymphoma (cHL) and mediastinal large B-cell lymphoma (MLBCL) are lymphoid malignancies with certain shared clinical, histologic, and molecular features. Primary cHLs and MLBCLs include variable numbers of malignant cells within an inflammatory infiltrate, suggesting that these tumors escape immune surveillance. Herein, we integrate high-resolution copy number data with transcriptional profiles and identify the immunoregulatory genes, PD-L1 and PD-L2, as key targets at the 9p24.1 amplification peak in HL and MLBCL cell lines. We extend these findings to laser-capture microdissected primary Hodgkin Reed-Sternberg cells and primary MLBCLs and find that programmed cell death-1 (PD-1) ligand/9p24.1 amplification is restricted to nodular sclerosing HL, the cHL subtype most closely related to MLBCL. Using quantitative immunohistochemical methods, we document the association between 9p24.1 copy number and PD-1 ligand expression in primary tumors. In cHL and MLBCL, the extended 9p24.1 amplification region also included the Janus kinase 2 (JAK2) locus. Of note, JAK2 amplification increased protein expression and activity, specifically induced PD-1 ligand transcription and enhanced sensitivity to JAK2 inhibition. Therefore, 9p24.1 amplification is a disease-specific structural alteration that increases both the gene dosage of PD-1 ligands and their induction by JAK2, defining the PD-1 pathway and JAK2 as complementary rational therapeutic targets.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115, USA.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Green
authors.forename: Stefano
authors.initials: S
authors.lastname: Monti
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Rodig
authors.forename: Przemyslaw
authors.initials: P
authors.lastname: Juszczynski
authors.forename: Treeve
authors.initials: T
authors.lastname: Currie
authors.forename: Evan
authors.initials: E
authors.lastname: O'Donnell
authors.forename: Bjoern
authors.initials: B
authors.lastname: Chapuy
authors.forename: Kunihiko
authors.initials: K
authors.lastname: Takeyama
authors.forename: Donna
authors.initials: D
authors.lastname: Neuberg
authors.forename: Todd R
authors.initials: TR
authors.lastname: Golub
authors.forename: Jeffery L
authors.initials: JL
authors.lastname: Kutok
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Shipp
mesh_terms: D015703:Antigens, CD / Q000235:genetics*; D060890:B7-H1 Antigen; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics*; D018628:Gene Dosage; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006689:Hodgkin Disease / Q000235:genetics*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics*; D061027:Programmed Cell Death 1 Ligand 2 Protein; D014407:Tumor Cells, Cultured
chemical_list: D015703:Antigens, CD; D060890:B7-H1 Antigen; C423236:CD274 protein, human; D036341:Intercellular Signaling Peptides and Proteins; C556977:PDCD1LG2 protein, human; D061027:Programmed Cell Death 1 Ligand 2 Protein; D053614:Janus Kinase 2