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R.A.L. de Groen et al.
MYD88(L265P) in NF-κB (nuclear factor kappa-light- chain-enhancer of activated B cells) activation and its association with the B-cell receptor (BCR) cascade. In addition, we address the clinical importance of MYD88(L265P), including its prevalence across B-NHL subtypes, its predictive significance in patients’ outcome, and its potential as a therapeutic target.
Oncogenic mechanisms of MYD88(L265P)
growth factor beta-activated kinase 1 (TAK1).5 Activated TAK1 continues signaling through the mitogen-activated protein kinase (MAPK) signaling cascade and cooperates with TAK1-binding protein (TAB) to activate the inhibitor of the NF-κB kinase (IKK) complex.
Canonical NF-κB signaling
In normal physiology, MYD88 acts as a signaling adap-
The IKK complex consists of the kinase subunits IKKa and IKKβ and the regulatory subunit NF-κB essential modulator. After activation, this complex phosphorylates the inhibitor of NF-κB (IκB) proteins that are bound to NF-κB, which prevent migration of NF-κB to the nucleus. Phosphorylation of these IκB proteins results in ubiquity- lation and proteasomal degradation of IκB and release of the NF-κB subunits. Subsequently, the NF-κB subunits, including RELA (p65)-p50 in the classical pathway and RELB-p52 in the alternative pathway, migrate to the nucleus where they bind to specific DNA-binding sites and induce increased expression of genes involved in B- cell proliferation and survival. In addition, expression of these genes is increased through interactions between the NF-κB subunits and other transcription factors, such as E1A binding protein P300 (EP300) and CREB binding pro- tein(CREBBP).6
tor in the canonical NF-κB pathway (Figure 1). This path- way is activated upon recognition of pathogen-associated molecular patterns (PAMP) by receptors containing a toll/interleukin-1 receptor (TIR) domain, such as toll-like receptors (TLR) and the interleukin receptors 1 (IL-1R) and 18 (IL-18R). After ligand binding, the TIR domain of these receptors interacts with the TIR domain of MYD884 and this process initiates the formation of the so-called ‘myddosome complex’. For this complex, activated MYD88 recruits IL-1R associated kinase 4 (IRAK4), a ser- ine-threonine kinase, and together they phosphorylate IRAK1 or IRAK2. Phosphorylated IRAK1 and IRAK2 interact with tumor necrosis factor receptor-associated factor 6 (TRAF6), resulting in activation of transforming
In the case of MYD88(L265P), the TIR domain of MYD88, in which L265P resides, is more highly activated compared with wildtype MYD88 and this increases downstream signaling and formation of the myddosome complex.2 Henceforth, MYD88(L265P) preferentially and
Figure 1. The role of MYD88 signaling in normal physiology and lymphomagenesis. Recognition of pathogens by TLR, IL1R, and IL-18R induces an immune response through activation of MYD88 and generates the myddosome complex with IRAK4 and IRAK1 or IRAK2, which is stabilized by HSP110. IRAK1 and IRAK2 activate the MAPK and NF-κB pathways through TRAF6 and TAK1, causing proliferation and survival of B cells. MYD88(L265P) allows for increased formation of the myddosome complex, preferentially with IRAK1, and constitutively activates the NF-κB pathway. In addition, the formation of the My-T-BCR supercomplex leads to increased acti- vation of mTOR and the CBM complex, promoting lymphomagenesis. Lastly, constitutively active NF-κB increases autocrine signaling of IL-6 and IL-10, which further promote B-cell proliferation and survival via the alternative JAK/STAT signaling cascade.
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haematologica | 2019; 104(12)