title: JAK2 rearrangements, including the novel SEC31A-JAK2 fusion, are recurrent in classical Hodgkin lymphoma.
abstract: The genetics of classical Hodgkin lymphoma (cHL) is poorly understood. The finding of a JAK2-involving t(4;9)(q21;p24) in 1 case of cHL prompted us to characterize this translocation on a molecular level and to determine the prevalence of JAK2 rearrangements in cHL. We showed that the t(4;9)(q21;p24) leads to a novel SEC31A-JAK2 fusion. Screening of 131 cHL cases identified 1 additional case with SEC31A-JAK2 and 2 additional cases with rearrangements involving JAK2. We demonstrated that SEC31A-JAK2 is oncogenic in vitro and acts as a constitutively activated tyrosine kinase that is sensitive to JAK inhibitors. In vivo, SEC31A-JAK2 was found to induce a T-lymphoblastic lymphoma or myeloid phenotype in a murine bone marrow transplantation model. Altogether, we identified SEC31A-JAK2 as a chromosomal aberration characteristic for cHL and provide evidence that JAK2 rearrangements occur in a minority of cHL cases. Given the proven oncogenic potential of this novel fusion, our studies provide new insights into the pathogenesis of cHL and indicate that in at least some cases, constitutive activation of the JAK/STAT pathway is caused by JAK2 rearrangements. The finding that SEC31A-JAK2 responds to JAK inhibitors indicates that patients with cHL and JAK2 rearrangements may benefit from targeted therapies.
authors.affiliation: Center for Human Genetics, Katholieke Universiteit Leuven, Leuven, Belgium.
authors.forename: Katrien
authors.initials: K
authors.lastname: Van Roosbroeck
authors.forename: Luk
authors.initials: L
authors.lastname: Cox
authors.forename: Thomas
authors.initials: T
authors.lastname: Tousseyn
authors.forename: Idoya
authors.initials: I
authors.lastname: Lahortiga
authors.forename: Olga
authors.initials: O
authors.lastname: Gielen
authors.forename: Barbara
authors.initials: B
authors.lastname: Cauwelier
authors.forename: Pascale
authors.initials: P
authors.lastname: De Paepe
authors.forename: Gregor
authors.initials: G
authors.lastname: Verhoef
authors.forename: Peter
authors.initials: P
authors.lastname: Marynen
authors.forename: Peter
authors.initials: P
authors.lastname: Vandenberghe
authors.forename: Chris
authors.initials: C
authors.lastname: De Wolf-Peeters
authors.forename: Jan
authors.initials: J
authors.lastname: Cools
authors.forename: Iwona
authors.initials: I
authors.lastname: Wlodarska
mesh_terms: D000328:Adult; D000369:Aged, 80 and over; D000818:Animals; D016026:Bone Marrow Transplantation; D002894:Chromosomes, Human, Pair 4; D002899:Chromosomes, Human, Pair 9; D004195:Disease Models, Animal; D005260:Female; D015321:Gene Rearrangement / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000453:epidemiology; D057809:HEK293 Cells; D006689:Hodgkin Disease / Q000453:epidemiology / Q000235:genetics*; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics*; D008297:Male; D051379:Mice; D008875:Middle Aged; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics; D015995:Prevalence; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D014178:Translocation, Genetic; D033921:Vesicular Transport Proteins / Q000235:genetics*; D055815:Young Adult
chemical_list: D015514:Oncogene Proteins, Fusion; C507455:SEC31A protein, human; D033921:Vesicular Transport Proteins; D011505:Protein-Tyrosine Kinases; C507924:JAK2 protein, human; D053614:Janus Kinase 2