• What is MYD88?
  • MYD88 in Waldenstrom Macroglobulinemia
  • MYD88 c.794T>C (L265P)
  • Clinical Trials

MYD88

Myeloid differentiation primary response 88 (MYD88) is a gene that encodes a cytosolic adapter protein necessary for both innate and adaptive immune response. Missense mutations, nonsense mutations, silent mutations, and in-frame deletions are observed in cancers such as leukemias, lung cancer, and skin cancer.

Related Pathways

Last Updated: December 4, 2015

MYD88 in Waldenstrom Macroglobulinemia

MYD88 is mutated in 90–95% of Waldenstrom Macroglobulinemia patients (Growkova et al. 2017; Treon et al. 2011) with the predominant mutation being an L265P mutation. There are ongoing efforts to target MYD88 L265P as it has been defined as an early oncogenic event in the development of WM (Jimenez et al. 2013; Mori et al. 2013; Varettoni et al. 2013).

Last Updated: February 26, 2018

MYD88 c.794T>C (L265P) Mutation in Waldenstrom Macroglobulinemia

Properties
Location Toll-IL1 receptor domain (Exon 5; Ngo et al. 2011)
Frequency of MYD88 mutations in WM 90–95% (Growkova et al 2017; Treon et al 2011)
Frequency of MYD88 L265P mutations in WM 80–93% (Lian et al 2013; Poulain et al 2013)
Implications for Targeted Therapeutics
Response to ibrutinib Confers increased sensitivitya
Response to rituximab Confers increased sensitivityb

The MYD88 L265P mutation results in an amino acid substitution at position 265 in exon 5, from a leucine (L) to a proline (P). This mutation occurs within the Toll-IL1 receptor domain of the gene and is predominantly seen in patients diagnosed with Waldenstrom Macroglobulinemia (WM)(Growkova et al 2017; Treon et al 2011). MYD88 L265P is a gain of function mutation which results in increased cell survival by increasing NF-κB activity, JAK-STAT3 signaling, and consequently cytokine production (Ngo et al. 2011). The presence of L265P mutation confers a higher probability of disease progression and a poor response to therapies, making it an adverse prognostic factor as compared to wild-type gene (Patkar et al 2013; Treon et al 2014).

a The BTK inhibitor ibrutinib was FDA approved for treating WM in 2015 (FDA, 2017). Phase II trials showed that patients treated with ibrutinib displayed an overall response rate of 90.5%, and an overall survival rate of 95.2% (Treon et al. 2015).

b Phase II trials using combination therapy of rituximab (an anti-CD20 antibody) with bortezomib and dexamethasone resulted in prolonged progression free survival and an improved survival rate compared to untreated patients (Dimopoulos et al. 2013; Treon et al. 2009).

Last Updated: February 26, 2018

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