title: Selective JAK2 inhibition specifically decreases Hodgkin lymphoma and mediastinal large B-cell lymphoma growth in vitro and in vivo.
abstract: OBJECTIVE
  Classical Hodgkin lymphoma (cHL) and primary mediastinal large B-cell lymphoma (MLBCL) share similar histologic, clinical, and genetic features. In recent studies, we found that disease-specific chromosome 9p24.1/JAK2 amplification increased JAK2 expression and activity in both cHL and MLBCL. This prompted us to assess the activity of a clinical grade JAK2 selective inhibitor, fedratinib (SAR302503/TG101348), in in vitro and in vivo model systems of cHL and MLBCL with defined JAK2 copy numbers.
  
  
  METHODS
  We used functional and immunohistochemical analyses to investigate the preclinical activity of fedratinib and associated biomarkers in cell lines and murine xenograft models of cHL and MLBCL with known 9p24.1/JAK2 copy number.
  
  
  RESULTS
  Chemical JAK2 inhibition decreased the cellular proliferation of cHL and MLBCL cell lines and induced their apoptosis. There was an inverse correlation between 9p24.1/JAK2 copy number and the EC50 of fedratinib. Chemical JAK2 inhibition decreased phosphorylation of JAK2, STAT1, STAT3, and STAT6 and reduced the expression of additional downstream targets, including PD-L1, in a copy number-dependent manner. In murine xenograft models of cHL and MLBCL with 9p24.1/JAK2 amplification, chemical JAK2 inhibition significantly decreased JAK2/STAT signaling and tumor growth and prolonged survival. In in vitro and in vivo studies, pSTAT3 was an excellent biomarker of baseline JAK2 activity and the efficacy of chemical JAK2 inhibition.
  
  
  CONCLUSIONS
  In in vitro and in vivo analyses, cHL and MLBCL with 9p24.1/JAK2 copy gain are sensitive to chemical JAK2 inhibition suggesting that clinical evaluation of JAK2 blockade is warranted.
authors.affiliation: Authors' Affiliations: Medical Oncology, Dana-Farber Cancer Institute; Section of Computational Biomedicine, Boston University School of Medicine; and Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Yansheng
authors.initials: Y
authors.lastname: Hao
authors.affiliation: Authors' Affiliations: Medical Oncology, Dana-Farber Cancer Institute; Section of Computational Biomedicine, Boston University School of Medicine; and Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Bjoern
authors.initials: B
authors.lastname: Chapuy
authors.affiliation: Authors' Affiliations: Medical Oncology, Dana-Farber Cancer Institute; Section of Computational Biomedicine, Boston University School of Medicine; and Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Stefano
authors.initials: S
authors.lastname: Monti
authors.affiliation: Authors' Affiliations: Medical Oncology, Dana-Farber Cancer Institute; Section of Computational Biomedicine, Boston University School of Medicine; and Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Heather H
authors.initials: HH
authors.lastname: Sun
authors.affiliation: Authors' Affiliations: Medical Oncology, Dana-Farber Cancer Institute; Section of Computational Biomedicine, Boston University School of Medicine; and Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Rodig
authors.affiliation: Authors' Affiliations: Medical Oncology, Dana-Farber Cancer Institute; Section of Computational Biomedicine, Boston University School of Medicine; and Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts Margaret_shipp@dfci.harvard.edu.
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Shipp
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D060890:B7-H1 Antigen / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018628:Gene Dosage / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D006689:Hodgkin Disease / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control; D006801:Humans; D007150:Immunohistochemistry; D053631:Interleukin Receptor Common gamma Subunit / Q000172:deficiency / Q000235:genetics; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control; D008297:Male; D008479:Mediastinal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D011759:Pyrrolidines / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050791:STAT Transcription Factors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D000096926:Benzenesulfonamides
chemical_list: D060890:B7-H1 Antigen; D053631:Interleukin Receptor Common gamma Subunit; D053614:Janus Kinase 2; D011759:Pyrrolidines; D050791:STAT Transcription Factors; D013449:Sulfonamides; C423236:CD274 protein, human; C507942:Il2rg protein, mouse; C528327:fedratinib; D000096926:Benzenesulfonamides; C507924:JAK2 protein, human