期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2014
卷号：111
期号：44
页码：E4762-E4768
DOI：10.1073/pnas.1405423111
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificancePrimary effusion lymphoma (PEL) is an AIDS-defining cancer. It is associated with Kaposi sarcoma-associated herpesvirus. To date, no sequencing studies have been conducted for this cancer. We used X chromosome-targeted next-generation sequencing to identify 33 genes with coding region mutations in 100% of cases, including in interleukin 1 receptor-associated kinase 1 (IRAK1). IRAK1 kinase modulates toll-like receptor signaling-mediated immune signaling. It binds to MyD88 adapter protein, which is mutated in a subset of diffuse large B-cell lymphomas. IRAK1, however, had not been linked to cancer. This IRAK1 mutant is constitutively active and essential for PEL survival. This highlights the importance of innate immunity signaling as drivers for cancer, particularly those caused by viruses. It also suggests IRAK1 kinase may be a potential target for therapy. Primary effusion lymphoma (PEL) is an AIDS-defining cancer. All PELs carry Kaposi sarcoma-associated herpesvirus (KSHV). X chromosome-targeted sequencing of PEL identified 34 common missense mutations in 100% of cases. This included a Phe196Ser change in the interleukin 1 receptor-associated kinase 1 (IRAK1). The mutation was verified in primary PEL exudates. IRAK1 is the binding partner of MyD88, which is mutated in a fraction of Waldenstrom macroglobulinemia. Together, these two mediate toll-like receptor (TLR) signaling. IRAK1 was constitutively phosphorylated in PEL and required for survival, implicating IRAK1 and TLR signaling as a driver pathway in PEL and as a new drug development target.
