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. (Blood. 2011;117(15): 4056-4064)

Ruxolitinib as potential targeted therapy for patients with JAK2 rearrangements

“…Since aberrant activation of JAK2 has also been demonstrated in lymphoid disorders, e.g. by JAK2 rearrangement or SOCS1 mutation in lymphoma 7,16 and CRLF2, IL7R and JAK family mutations in acute lymphoblastic leukemia, 17,18 it is possible that treatment with ruxolitinib will have wider potential applicability in addition to the treatment of patients with JAK2 rearrangement-positive MPN described here. …”

“…[1][2][3][4][5][6][7] Three fusion variants in MPN, namely PCM1-JAK2, BCR-JAK2 and ETV6-JAK2, are thought to be constitutively activated drivers of the disease process analogous to BCR-ABL1 in chronic myeloid leukemia. JAK2-rearranged malignancies are typically aggressive and, apart from stem cell transplantation, current therapies have limited efficacy.…”

EBV-Positive and EBV-Negative Posttransplant Diffuse Large B Cell Lymphomas Have Distinct Genomic and Transcriptomic Features

“…Expression data, however, point to PDLCD1LG2 as the target of this aberration. Patients with the 9p24.1 gain/amplification did not reveal particular clinical features, but their mean survival was slightly shorter than in the remaining EBV Copy number gain of 9p24.1 is a known aberration in lymphoma, particularly in primary mediastinal B cell lymphoma (PMBCL) and classic Hodgkin lymphoma (cHL) (14)(15)(16)(17). It was postulated that in PMBCL this aberration leads to increased dosage of both PDL1 and PDL2, and their induction by the neighboring JAK2 (14).…”

Honokiol Inhibits Constitutive and Inducible STAT3 Signaling via PU.1-Induced SHP1 Expression in Acute Myeloid Leukemia Cells

“…Constitutive activation of STAT signaling has often been discovered in hematopoietic malignancies including acute myeloid leukemia (AML), T-cell large granular lymphocytic leukemia, Hodgkin lymphoma and myeloproliferative neoplasm (Lin et al 2000;Van Roosbroeck et al 2011;Teramo et al 2013). Mutations of upstream receptors such as FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD), c-KIT, and granulocyte colony stimulating factor receptor (G-CSFR), and NRAS caused constitutive activation of STAT signaling, which finally resulted in uncontrolled proliferation and prevention of apoptosis in AML (Weiler et al 1996;Dong et al 1997;Stirewalt and Radich 2003;Bacher et al 2006).…”