Oncogenically active MYD88 mutations in human lymphoma

By Vu N. Ngo, R. Young, R. Schmitz, S. Jhavar, Wenming Xiao, K. Lim, H. Kohlhammer, Weihong Xu, Yandan Yang, Hong Zhao and 21 more. Nature, 2010

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The activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL) remains the least curable form of this malignancy despite recent advances in therapy. Constitutive nuclear factor (NF)-κB and JAK kinase signalling promotes malignant cell survival in these lymphomas, but the genetic basis for this signalling is incompletely understood. Here we describe the dependence of ABC DLBCLs on MYD88, an adaptor protein that mediates toll and interleukin (IL)-1 receptor signalling, and the discovery of highly recurrent oncogenic mutations affecting MYD88 in ABC DLBCL tumours. RNA interference screening revealed that MYD88 and the associated kinases IRAK1 and IRAK4 are essential for ABC DLBCL survival. High-throughput RNA resequencing uncovered MYD88 mutations in ABC DLBCL lines. Notably, 29% of ABC DLBCL tumours harboured the same amino acid substitution, L265P, in the MYD88 Toll/IL-1 receptor (TIR) domain at an evolutionarily invariant residue in its hydrophobic core. This mutation was rare or absent in other DLBCL subtypes and Burkitt’s lymphoma, but was observed in 9% of mucosa-associated lymphoid tissue lymphomas. At a lower frequency, additional mutations were observed in the MYD88 TIR domain, occurring in both the ABC and germinal centre B-cell-like (GCB) DLBCL subtypes. Survival of ABC DLBCL cells bearing the L265P mutation was sustained by the mutant but not the wild-type MYD88 isoform, demonstrating that L265P is a gain-of-function driver mutation. The L265P mutant promoted cell survival by spontaneously assembling a protein complex containing IRAK1 and IRAK4, leading to IRAK4 kinase activity, IRAK1 phosphorylation, NF-κB signalling, JAK kinase activation of STAT3, and secretion of IL-6, IL-10 and interferon-β. Hence, the MYD88 signalling pathway is integral to the pathogenesis of ABC DLBCL, supporting the development of inhibitors of IRAK4 kinase and other components of this pathway for the treatment of tumours bearing oncogenic MYD88 mutations.

Subfields: Cancer Research, Immunology, Pathology and Forensic Medicine

View Paper: https://www.semanticscholar.org/paper/b18ac9df40325ab77e356f65f22a3636602c5d64

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Citations in the corpus

A Probabilistic Classification Tool for Genetic Subtypes of Diffuse Large B Cell Lymphoma with Therapeutic Implications (2020, background): “The MYD88 isoform in MCDmodels spontaneously coordinates a signaling complex involving IRAK1 and IRAK4 (Ngo et al., 2011) supporting the evaluation of IRAK4 inhibitors in MCD, especially in combination with a BTK inhibitor (Kelly et al.”
Evolution and impact of subclonal mutations in chronic lymphocytic leukemia (2013, positive): “We identified driver mutations that were consistently clonal (del(13q), MYD88, and trisomy 12 (Figure 3A), which appear to be relatively specific drivers of CLL or B cell malignancies (Beroukhim et al., 2010; Döhner et al., 2000; Ngo et al., 2010).”
Lessons from the cancer genome. (2013, neutral): “Dulak, personal communication),MYD88 in diffuse large B cell lymphoma (activates NFkB signaling) (Ngo et al., 2011), and PREX2 in melanoma (a guanine nucleotide exchange factor that controls RAC/PAK and PI3K signaling) (Berger et al.”
Integrated genomic analysis identifies recurrent mutations and evolution patterns driving the initiation and progression of follicular lymphoma (2013, neutral): “Four of the five MYD88 mutations identified were restricted to the transformation biopsy, of which none harbored the L265P mutation common to other B-cell lymphomas 30,37 (Supplementary Fig.”