Role of 1q21 in Multiple Myeloma: From Pathogenesis to Possible Therapeutic Targets

Abstract

Multiple myeloma (MM) is characterized by an accumulation of malignant plasma cells (PCs) in the bone marrow (BM). The amplification of 1q21 is one of the most common cytogenetic abnormalities occurring in around 40% of de novo patients and 70% of relapsed/refractory MM. Patients with this unfavorable cytogenetic abnormality are considered to be high risk with a poor response to standard therapies. The gene(s) driving amplification of the 1q21 amplicon has not been fully studied. A number of clear candidates are under investigation, and some of them (IL6R, ILF2, MCL-1, CKS1B and BCL9) have been recently proposed to be potential drivers of this region. However, much remains to be learned about the biology of the genes driving the disease progression in MM patients with 1q21 amp. Understanding the mechanisms of these genes is important for the development of effective targeted therapeutic approaches to treat these patients for whom effective therapies are currently lacking. In this paper, we review the current knowledge about the pathological features, the mechanism of 1q21 amplification, and the signal pathway of the most relevant candidate genes that have been suggested as possible therapeutic targets for the 1q21 amplicon.

Keywords: 1q21; BCL9; CKS1B; IL6R; ILF2; MCL-1; amplification; chromosome aberrations; multiple myeloma.

Figure 1

Genetic events from initiation to progression in multiple myeloma pathogenesis. Chromosomal aberrations involving immunoglobulin heavy chain (IGH) at the 14q32 region and the hyperdiploid are considered primary translocations as they are mutually exclusive and present in asymptomatic stages. Secondary aberrations follow primary events contributing to tumor progression and relapse. Secondary events cooperate with primary events to produce the malignant PC phenotype. The progression from MGUS-SMM to MM is associated with RAS mutation, MYC overexpression, and amplification of 1q21. Incidence of MYC translocation, deletion of 17p, and recurrent mutations increased as disease progressed. The initiation of aberrant clones at the onset of the disease is indicated in yellow. Red indicates the accumulation of malignant clones during disease progression. Percentage is indicated at new diagnosis. Asterisk indicates P53 mutation.

Figure 2

Schematic representation of chromosome 1 indicating the location of the possible genetic driver genes in this region, denoted by colored lines. The amplification of the 1q21 region results in the simultaneous overexpression of several genes leading to disease progression, MM cell survival, and an increase in genomic instability. BCL9, B cell lymphoma 9; MCL-1, myeloid cell leukemia-1; ILF2, interleukin enhancer binding factor 2; IL6R, interleukin-6 receptor; and CKS1B, CDC28 protein kinase regulatory subunit 1B.