title: Activation of TAK1 by MYD88 L265P drives malignant B-cell Growth in non-Hodgkin lymphoma.
abstract: Massively parallel sequencing analyses have revealed a common mutation within the MYD88 gene (MYD88L265P) occurring at high frequencies in many non-Hodgkin lymphomas (NHLs) including the rare lymphoplasmacytic lymphoma, Waldenström's macroglobulinemia (WM). Using whole-exome sequencing, Sanger sequencing and allele-specific PCR, we validate the initial studies and detect the MYD88L265P mutation in the tumor genome of 97% of WM patients analyzed (n=39). Due to the high frequency of MYD88 mutation in WM and other NHL, and its known effects on malignant B-cell survival, therapeutic targeting of MYD88 signaling pathways may be clinically useful. However, we are lacking a thorough characterization of the role of intermediary signaling proteins on the biology of MYD88L265P-expressing B cells. We report here that MYD88L265P signaling is constitutively active in both WM and diffuse large B-cell lymphoma cells leading to heightened MYD88L265P, IRAK and TRAF6 oligomerization and NF-κB activation. Furthermore, we have identified the signaling protein, TAK1, to be an essential mediator of MYD88L265P-driven signaling, cellular proliferation and cytokine secretion in malignant B cells. Our studies highlight the biological significance of MYD88L265P in NHL and reveal TAK1 inhibition to be a potential therapeutic strategy for the treatment of WM and other diseases characterized by MYD88L265P.
authors: Division of Hematology, Mayo Clinic, Rochester, MN, USA.
authors: S M
authors: SM
authors: Ansell
authors: Division of Hematology, Mayo Clinic, Rochester, MN, USA.
authors: L S
authors: LS
authors: Hodge
authors: Division of Hematology, Mayo Clinic, Rochester, MN, USA.
authors: F J
authors: FJ
authors: Secreto
authors: Division of Hematology, Mayo Clinic, Rochester, MN, USA.
authors: M
authors: M
authors: Manske
authors: Division of Hematology, Mayo Clinic, Scottsdale, AZ, USA.
authors: E
authors: E
authors: Braggio
authors: Division of Hematology, Mayo Clinic, Rochester, MN, USA.
authors: T
authors: T
authors: Price-Troska
authors: Division of Hematology, Mayo Clinic, Rochester, MN, USA.
authors: S
authors: S
authors: Ziesmer
authors: Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA.
authors: Y
authors: Y
authors: Li
authors: Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA.
authors: S H
authors: SH
authors: Johnson
authors: Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA.
authors: S N
authors: SN
authors: Hart
authors: Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA.
authors: J-P A
authors: JP
authors: Kocher
authors: Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA.
authors: G
authors: G
authors: Vasmatzis
authors: Division of Hematology, Mayo Clinic, Jacksonville, FL, USA.
authors: A
authors: A
authors: Chanan-Kahn
authors: Division of Hematology, Mayo Clinic, Rochester, MN, USA.
authors: M
authors: M
authors: Gertz
authors: Division of Hematology, Mayo Clinic, Scottsdale, AZ, USA.
authors: R
authors: R
authors: Fonseca
authors: Division of Anatomic Pathology and Hematopathology, Mayo Clinic, Rochester, MN, USA.
authors: A
authors: A
authors: Dogan
authors: Division of Epidemiology, Mayo Clinic, Rochester, MN, USA.
authors: J R
authors: JR
authors: Cerhan
authors: Division of Hematology, Mayo Clinic, Rochester, MN, USA.
authors: A J
authors: AJ
authors: Novak