In this issue of Blood, Poulain et al demonstrate the high prevalence of the MYD88 L265P somatic mutation in patients with Waldenstrom macroglobulinemia (WM) and provide insight into its biological relevance in the growth and survival of WM.1 

Since the initial report by Treon et al2  of the existence of the MYD88 L265P somatic mutation in WM patients using whole genome sequencing (WGS), a flurry of recent studies have confirmed the high frequency of the MYD88 L265P somatic mutation in patients with WM and IgM monoclonal gammopathy of unknown significance (IgM MGUS) by Sanger, polymerase chain reaction (PCR), and allele-specific PCR (AS-PCR) assays3-8  (see table). These studies have also contributed to our understanding of how MYD88 L265P enables the expansion of WM cells and the potential for use in the diagnosis, treatment, and response assessment of WM.

The discovery of a mutation in MYD88 is significant given its role as an adaptor molecule in Toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) signaling. Following TLR or IL-1R stimulation, MYD88 is recruited to the activated receptor complex as a homodimer, which complexes with IL-1R–associated kinase (IRAK) 4 to activate IRAK1. Tumor necrosis factor receptor–associated factor 6 is then activated leading to nuclear factor κB (NF-κB) activation via IκBα phosphorylation. Similar to the findings by Ngo et al9  in MYD88 L265P–expressing activated B-cell–like (ABC) diffuse large B-cell lymphoma (DLBCL) cell lines, inhibition of MYD88/IRAK signaling attenuates NF-κB signaling and survival of MYD88 L265P–expressing WM cells.1,2,8,10  Correspondingly, WM cell survival is enhanced by MYD88 L265P overexpression. Additionally, Yang et al10  have shown that inhibition of MYD88 in L265P–expressing WM cells is accompanied by decreased activation of Bruton tyrosine kinase (BTK), whereas overexpression of MYD88 L265P enhances BTK phosphorylation. These studies also show that IRAK and BTK independently direct downstream NF-κB activation and combined use of IRAK and BTK inhibitors leads to synergistic tumor cell killing in MYD88 L265P–expressing WM cells. These studies would suggest a model wherein MYD88 L265P triggers NF-κB via dual, but independent pathways, which signal through BTK and/or IRAK1/IRAK4.

The likely role of MYD88 L265P as an early oncogenic event for the development of WM is raised by studies showing this somatic mutation in up to 80% of individuals with IgM MGUS2,4-7  (see table). The presence of MYD88 L265P in patients with IgM MGUS significantly increases the risk of malignant evolution as reported by Varettoni et al.6  IgM-MGUS patients with MYD88 L265P have higher levels of IgM, lower levels of IgG and IgA, and a higher incidence of Bence-Jones proteinuria at diagnosis.6  Other recurring somatic mutations have been revealed by WGS in WM patients, which could serve as triggers for progression from IgM MGUS to symptomatic WM.2  A multihit model could also explain why no significant differences in treatment response and progression-free and overall survival based solely on MYD88 mutation status determination were observed by Jimenez et al7  in a large series of WM patients. MYD88 mutation status does, however, separate patients across a few clinical characteristics including serum IgM (sIgM) levels, bone marrow (BM) disease involvement, peripheral blood lymphocytosis, and/or tumor cell expression of CD27.1,2,4,7 

The diagnostic discrimination of WM/lymphoplasmacytic lymphoma (LPL) vs marginal zone lymphomas (MZLs), IgM secreting myeloma (MM), and chronic lymphocytic leukemia (CLL) with plasmacytic differentiation can sometimes be difficult due to overlapping clinicopathological characteristics. MYD88 L265P can help distinguish WM/LPL from MZL, MM, and CLL, which show no or infrequent expression (3% to 9%) of this somatic mutation, with the possibility that many of these cases are WM/LPL.1-4,6-8  The expression of MYD88 L265P should, however, be considered supportive and not exclusively diagnostic of WM/LPL because its presence has also been demonstrated in other lymphomas including DLBCL (ABC subtype)10  and also does not discriminate IgM MGUS from WM, the latter requiring the presence of an infiltrate by histologic examination. However, higher levels of MYD88 L265P in BM B cells are associated with evolution to WM,4  and larger studies are needed clarify if quantitative PCR can be used to delineate IgM MGUS from WM, as well as IgM MGUS patients at higher risk of malignant progression.

The potential for MYD88 L265P to be exploited therapeutically in WM is suggested by studies showing that inhibition of MYD88 and downstream targets including IRAK1, IRAK4, BTK, and TAK1 can suppress downstream NF-κB signaling and/or induce WM cell killing.1,2,8,10  High rates of response were observed in an ongoing clinical trial with a BTK inhibitor in relapsed/refractory WM patients and may correlate with MYD88 status. These clinical findings may reflect the dependence of tumor growth and survival on MYD88 L265P–directed BTK activity as suggested by the work of Yang et al.10  Investigation of MYD88 mutation status may therefore help identify patients who could benefit with MYD88 path–targeted therapies.

The potential use of MYD88 L265P as a response tool was shown by both Xu et al4  and Jimenez et al7  using quantitative AS-PCR to follow changes in BM disease burden after treatment. Response assessment can often be difficult in WM patients due to dependence on serial sIgM measurements. Many agents used to treat WM discordantly affect sIgM levels relative to the underlying disease burden. Repeat BM biopsies are used to clarify such discordant responses and determine the need for changing therapeutic management. The use of quantitative PCR for MYD88 L265P could provide a faster and more cost-effective determination of such discordant findings relative to immunohistochemistry. Peripheral blood testing for MYD88 L265P may also be possible and adapted to a quantitative approach providing a noninvasive means for underlying tumor burden assessment.

In summary, MYD88 L265P is a widely prevalent somatic mutation in patients with WM and IgM MGUS, which can help differentiate these entities from overlapping B-cell disorders. MYD88 L265P promotes the growth and survival of WM cells and represents a novel target for WM therapy. Indeed, a new era is upon us with the opportunity to advance this new genomic finding into tools for diagnosis and response assessment, as well as therapies that will improve the lives of WM patients.

Conflict-of-interest disclosure: SPT has received research funding from Pharmacyclics, Inc. The remaining author declares no competing financial interests.

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