# MYD88 L265P and CXCR4 mutations

Source: https://onco.cc/terms/myd88-l265p/  
OnCo record `myd88-l265p` (Term). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

One letter change in MYD88 (L265P) keeps a B-cell survival signal permanently on; it is found in more than nine in ten Waldenström's macroglobulinaemia, most primary CNS and testicular lymphomas and a poor-risk group of DLBCL, and it predicts that BTK inhibitors will work, while a second mutation in CXCR4 predicts that they will work more slowly.

## Summary

What is measured: the MYD88 L265P point mutation and, alongside it, CXCR4 nonsense or frameshift mutations (S338X the commonest) and CD79B mutations. How: allele-specific PCR or next-generation sequencing on bone marrow in Waldenström's, on tumour tissue in lymphoma, and on cerebrospinal fluid or vitreous cell-free DNA in CNS and ocular lymphoma, where it helps make a diagnosis without a brain biopsy. Frequencies: Waldenström's 90 to 95 percent, IgM MGUS 50 to 80 percent, marginal zone lymphoma under 10 percent (so a wild-type result favours marginal zone over Waldenström's), primary CNS lymphoma 60 to 80 percent with CD79B, and the MCD or cluster 5 subgroup of activated B-cell DLBCL; CXCR4 mutations are subclonal and present in 30 to 40 percent of Waldenström's. What a result changes: in Waldenström's, MYD88-mutated disease responds best to ibrutinib, zanubrutinib and acalabrutinib (ASPEN compared zanubrutinib and ibrutinib), CXCR4-mutated disease responds more slowly and less deeply with more IgM flare, favouring zanubrutinib or bendamustine-rituximab and proteasome-inhibitor regimens, and MYD88 wild-type disease does poorly on BTK inhibitors, steering to chemo-immunotherapy; in CNS lymphoma it supports BTK inhibitor trials, and in MCD DLBCL ibrutinib added to R-CHOP helped younger patients in a PHOENIX subgroup. Where it matters: Waldenström's, primary CNS lymphoma, marginal zone lymphoma and DLBCL.

## Fields

- Kind: Term
- Last checked: 2026-09-17
- Also known as: MYD88; MYD88 L265P; MYD88 mutation; MYD88-mutated; MYD88 wild-type; MYD88wt; CXCR4 mutation; CXCR4 S338X; CXCR4 WHIM-like mutation; MYD88/CXCR4 genotype; CD79B mutation; MCD subtype DLBCL; cluster 5 DLBCL

## Notes

- The mechanism, and the primary figures. MYD88 is the adaptor of the toll-like and interleukin-1 receptors, and L265P sits at an evolutionarily invariant residue in the hydrophobic core of its TIR domain. The mutant assembles a signalling complex with IRAK1 and IRAK4 without any receptor signal, driving NF-kB and JAK kinase activity; activated B-cell-like lymphoma cells carrying it die when MYD88, IRAK1 or IRAK4 are knocked down, and the wild-type protein cannot rescue them, which is what makes it a gain-of-function driver rather than a passenger. The original series found it in 29% of activated B-cell-like diffuse large B-cell lymphomas, rarely or not at all in other subtypes and in Burkitt lymphoma, and in 9% of MALT lymphomas (Ngo 2011). In Waldenstrom macroglobulinaemia, whole-genome sequencing found it in all 10 patients with paired normal tissue, and Sanger sequencing in 49 of 54 patients and in 91% of all lymphoplasmacytic lymphoma including the non-IgM form, absent from paired normal tissue and from healthy donor B cells (Treon 2012). With CD79B mutation it defines the MCD genetic subtype of large B-cell lymphoma (Schmitz 2018).

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/MYD88
- Wikipedia: https://en.wikipedia.org/wiki/MYD88
- Ngo et al., Nature 2011: oncogenically active MYD88 mutations in human lymphoma: https://doi.org/10.1038/nature09671
- Treon et al., N Engl J Med 2012: MYD88 L265P somatic mutation in Waldenstrom macroglobulinaemia: https://doi.org/10.1056/NEJMoa1200710
- Schmitz et al., N Engl J Med 2018: genetics and pathogenesis of diffuse large B-cell lymphoma (574 biopsies; MCD, BN2, N1, EZB): https://doi.org/10.1056/NEJMoa1801445

## Connected records

- targets: [BTK (Bruton tyrosine kinase)](https://onco.cc/targets/btk/), [CD79b](https://onco.cc/targets/cd79b/), [CXCR4](https://onco.cc/targets/cxcr4/), [MYD88](https://onco.cc/targets/myd88/)
- drugs: [Acalabrutinib](https://onco.cc/drugs/acalabrutinib/), [Bendamustine](https://onco.cc/drugs/bendamustine/), [Ibrutinib](https://onco.cc/drugs/ibrutinib/), [Zanubrutinib](https://onco.cc/drugs/zanubrutinib/)
- terms: [Cell of origin (GCB vs ABC)](https://onco.cc/terms/cell-of-origin/), [Circulating tumour DNA (ctDNA)](https://onco.cc/terms/ctdna/), [LymphGen and the genetic clusters of large B-cell lymphoma](https://onco.cc/terms/lymphoma-bio-lymphgen/), [Next-generation sequencing (NGS)](https://onco.cc/terms/ngs/)
- cancers: [Diffuse large B-cell lymphoma](https://onco.cc/cancers/dlbcl/), [Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma)](https://onco.cc/cancers/malt-lymphoma/), [Intravascular large B-cell lymphoma](https://onco.cc/cancers/intravascular-large-b-cell-lymphoma/), [Marginal zone lymphoma](https://onco.cc/cancers/marginal-zone-lymphoma/), [Non-Hodgkin lymphoma (all types)](https://onco.cc/cancers/non-hodgkin-lymphoma/), [Primary CNS lymphoma](https://onco.cc/cancers/primary-cns-lymphoma/), [Primary large B-cell lymphoma of the testis](https://onco.cc/cancers/primary-testicular-lymphoma/), [Waldenström macroglobulinaemia](https://onco.cc/cancers/waldenstrom/)
- pathways: [B-cell receptor / BTK signalling (to NF-κB)](https://onco.cc/pathways/bcr-signalling/), [Inflammation & NF-κB](https://onco.cc/pathways/inflammation-nfkb/)
- biomarkers: [CD79B ITAM mutation](https://onco.cc/biomarkers/cd79b-itam-mutation/)

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