Candidate genes of Waldenström’s macroglobulinemia: current evidence and research

Giada Bianchi,¹ Antonio Sacco,¹ Shaji Kumar,² Giuseppe Rossi,³ Irene Ghobrial,¹ Aldo Roccaro<sup>1

1</sup>Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, ²Division of Hematology, Mayo Clinic, Rochester, MN, USA; ³Department of Hematology, Spedali Civili di Brescia, Brescia, Italy

Abstract: Waldenström’s macroglobulinemia (WM) is a relatively uncommon, indolent malignancy of immunoglobulin M-producing B cells. The World Health Organization classifies it as a lymphoplasmacytic lymphoma and patients typically present with anemia, hepatosplenomegaly and diffuse lymphadenopathies. Historically, the genetic characterization of the disease has been hampered by the relatively low proliferative rate of WM cells, thus making karyotyping challenging. The use of novel technologies such as fluorescence in situ hybridization, gene array, and whole genome sequencing has contributed greatly to establishing candidate genes in the pathophysiology of WM and to identifying potential treatment targets, such as L265P MYD88. The discovery of microRNAs and the recognition of epigenetics as a major modulatory mechanism of oncogene expression and/or oncosuppressor silencing have aided in further understanding the pathogenesis of WM. Once thought to closely resemble multiple myeloma, a cancer of terminally differentiated, immunoglobulin-secreting plasma cells, WM appears to genetically cluster with other indolent B-cell lymphomas such as chronic lymphocytic leukemia/small cell lymphoma. The relative high incidence of familial cases of WM and other B-cell malignancies has been helpful in identifying high-risk gene candidates. In this review, we focus on the established genes involved in the pathogenesis of WM, with special emphasis on the key role of derangement of the nuclear factor kappa B signaling pathway and epigenetic mechanisms.

Keywords: genetics, familial cases, NF-κB, whole genome sequencing, MYD88