MYD88 L265P Mutation in Lymphoid Malignancies.

Xinfang Yu,Wei Li,Ken H Young,Qipan Deng,Yong Li,Ling Li,Mingzhi Zhang,Eric D Hsi

doi:10.1158/0008-5472.can-18-0215

Abstract

Next-generation sequencing has revealed cancer genomic landscapes, in which over 100 driver genes that, when altered by intragenic mutations, can promote oncogenesis. MYD88 is a driver gene found in hematologic B-cell malignancies. A missense mutation (L265P) changing leucine at position 265 to proline in MYD88 is found in ∼90% of Waldenström macroglobulinemia (WM) cases and in significant portions of activated B-cell diffuse large B-cell lymphomas and IgM monoclonal gammopathy of undetermined significance. Few cancers such as WM have a single amino acid substitution in one gene like MYD88 L265P that occurs in ∼90% of cases, making WM paradigmatic for study of a single causative mutation in oncogenesis. In this review, we summarize the frequency and cancer spectrum of MYD88 L265P and its downstream effects in lymphoid cancers. Malignant B cells with MYD88 L265P are likely transformed from IgM-producing B cells either in response to T-cell-independent antigens or in response to protein antigens before class switching. We also discuss therapeutic strategies that include targeting Bruton tyrosine kinase and other kinases, interfering with the assembly of MYD88 and its interacting partners, and MYD88 L265P-specific peptide-based immunotherapy. Cancer Res; 78(10); 2457-62. ©2018 AACR.

Highlights

Myeloid differentiation factor 88 (MYD88) was discovered in the 1990s as a primary differentiation response gene in myeloid precursors that was activated following terminal differentiation and growth arrest induced by IL6 [1, 2]
Recurrent MYD88 L265P mutation was first found in diffuse large B-cell lymphoma (DLBCL), which can be classified into two major molecular subtypes based on cell of origin [11]
We summarize the MYD88 L265P mutation frequency rates in different B-cell neoplasms: MYD88 L265P mutation occurs frequently in Waldenstro€m macroglobulinemia (WM) (87%), primary DLBCL of the central nerve system (CNS; 70%), cutaneous DLBCL, leg-type (54%), IgM MGUS (52%), testicular DLBCL (74%), and activated B-cell–like (ABC)-DLBCL (24%; Fig. 1A; Supplementary Table S1)

Summary

Introduction

Myeloid differentiation factor 88 (MYD88) was discovered in the 1990s as a primary differentiation response gene in myeloid precursors that was activated following terminal differentiation and growth arrest induced by IL6 [1, 2]. Malignant B cells with MYD88 L265P are likely transformed from IgM-producing B cells either in response to T-cell–independent antigens or in response to protein antigens before class switching. Recurrent MYD88 L265P mutation was first found in diffuse large B-cell lymphoma (DLBCL), which can be classified into two major molecular subtypes based on cell of origin [11].

Results

Conclusion