Abstract
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 Waldenström 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.
Keywords:
IRAK; Kaposi sarcoma; herpesviruses; myd88; primary effusion lymphoma.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Cell Line, Tumor
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Herpesviridae Infections / genetics
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Herpesviridae Infections / metabolism*
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Herpesviridae Infections / pathology
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Herpesvirus 8, Human*
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Humans
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Interleukin-1 Receptor-Associated Kinases / genetics
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Interleukin-1 Receptor-Associated Kinases / metabolism*
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Lymphoma, Primary Effusion / genetics
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Lymphoma, Primary Effusion / metabolism*
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Lymphoma, Primary Effusion / pathology
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Lymphoma, Primary Effusion / virology
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Mutation*
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Myeloid Differentiation Factor 88 / genetics
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Myeloid Differentiation Factor 88 / metabolism
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Neoplasm Proteins / genetics
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Neoplasm Proteins / metabolism*
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Signal Transduction*
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Toll-Like Receptors / genetics
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Toll-Like Receptors / metabolism
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Waldenstrom Macroglobulinemia / genetics
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Waldenstrom Macroglobulinemia / metabolism
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Waldenstrom Macroglobulinemia / pathology
Substances
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MYD88 protein, human
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Myeloid Differentiation Factor 88
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Neoplasm Proteins
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Toll-Like Receptors
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IRAK1 protein, human
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Interleukin-1 Receptor-Associated Kinases