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MYD88 in the driver’s seat of B-cell lymphomagenesis: from molecular mechanisms to clinical implications
Ferrata Storti Foundation
Haematologica 2019 Volume 104(12):2337-2348
Ruben A.L. de Groen,1 Anne M.R. Schrader,2 Marie José Kersten,3,4,5 Steven T. Pals3,5,6 and Joost S.P. Vermaat1
1Department of Hematology, Leiden University Medical Center, Leiden; 2Department of Pathology, Leiden University Medical Center, Leiden; 3Department of Hematology, Amsterdam University Medical Center, University of Amsterdam, Amsterdam; 4Lymphoma and Myeloma Center Amsterdam-LYMMCARE, Amsterdam; 5Cancer Center Amsterdam, Amsterdam and 6Department of Pathology, Amsterdam University Medical Center, Amsterdam, the Netherlands
ABSTRACT
More than 50 subtypes of B-cell non-Hodgkin lymphoma (B-NHL) are recognized in the most recent World Health Organization clas- sification of 2016. The current treatment paradigm, however, is largely based on ‘one-size-fits-all’ immune-chemotherapy. Unfortunately, this therapeutic strategy is inadequate for a significant number of patients. As such, there is an indisputable need for novel, preferably targeted, thera- pies based on a biologically driven classification and risk stratification. Sequencing studies identified mutations in the MYD88 gene as an impor- tant oncogenic driver in B-cell lymphomas. MYD88 mutations constitutive- ly activate NF-κB and its associated signaling pathways, thereby promoting B-cell proliferation and survival. High frequencies of the hotspot MYD88(L265P) mutation are observed in extranodal diffuse large B-cell lymphoma and Waldenström macroglobulinemia, thereby demonstrating this mutation's potential as a disease marker. In addition, the presence of mutant MYD88 predicts survival outcome in B-NHL subtypes and it pro- vides a therapeutic target. Early clinical trials targeting MYD88 have shown encouraging results in relapsed/refractory B-NHL. Patients with these disor- ders can benefit from analysis for the MYD88 hotspot mutation in liquid biopsies, as a minimally invasive method to demonstrate treatment response or resistance. Given these clear clinical implications and the crucial role of MYD88 in lymphomagenesis, we expect that analysis of this gene will increasingly be used in routine clinical practice, not only as a diagnostic classifier, but also as a prognostic and therapeutic biomarker directing pre- cision medicine. This review focuses on the pivotal mechanistic role of mutated MYD88 and its clinical implications in B-NHL.
Introduction
With the introduction of high-throughput, next-generation sequencing, many studies have aimed to explain the diverse biology, clinical course, prognosis, and therapeutic response of B-cell non-Hodgkin lymphoma (B-NHL). This has increased our knowledge of lymphomagenesis by identifying many novel somatic alterations that affect signaling pathways involved in several B-NHL subtypes. In this rapidly evolving molecular landscape, it is important to translate newly obtained genetic knowledge directly into clinical benefit for patients.1
Ngo et al. were the first to identify an oncogenic, non-synonymous, gain-of- function mutation in myeloid differentiation primary response 88 (MYD88), lead- ing to an amino-acid change of leucine to proline at position 265 (NM_002468.5, also referred to as position 273 in NM_001172567) of MYD88 [MYD88(L265P)].2 Other recurrent mutations in MYD88 were likewise identified; however, the impact of these mutations has been difficult to establish due to their low preva- lence.3 This review, therefore, focuses on the present understanding of the role of
Correspondence:
JOOST S.P. VERMAAT
j.s.p.vermaat@lumc.nl
Received: May 17, 2019. Accepted: September 19, 2019. Pre-published: November 7, 2019.
doi:10.3324/haematol.2019.227272
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/104/12/2337
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