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.

The adverse impact of a gain in chromosome 1q on the prognosis of multiple myeloma treated with bortezomib-based regimens: A retrospective single-center study in China

“…+1q is one of the most important chromosomal changes in differing stages of myeloma. From monoclonal gammopathy of undetermined significance, smoldering multiple myeloma, and newly diagnosed MM to relapsed and refractory multiple myeloma, the rate of +1q increases, which implies a relationship between +1q and disease progression ( 11 ), which might be due to the derangement of genes located on 1q21, including MCL-1, IL-6R, and CKS1B, all of which are closely related to myeloma prognosis ( 11 , 12 ). The impact of +1q on the prognosis is still unclear and has not been incorporated into the high-risk factors in most guidelines.…”

Pathogenesis and treatment of multiple myeloma

“…25 The amplification of 1q21 exists in a certain portion of MM patients, and this unfavorable cytogenetic abnormality has been associated with poor response to standard treatment. 26 The frequency of somatic mutations varies among patients. One study found that KRAS and NRAS mutated exclusively in MM patients, 21.2 and 19.4% in 463 patients, respectively.…”

“…Other chromosomal abnormalities observed in MM patients include loss of the short arm of chromosome 1 (del(1p)), deletion of the long arm of chromosome 13 (del(13q)), and gain of the long arm of chromosome 1 (gain(1q)) 25 . The amplification of 1q21 exists in a certain portion of MM patients, and this unfavorable cytogenetic abnormality has been associated with poor response to standard treatment 26 …”

Increased Expression of SETDB1 Predicts Poor Prognosis in Multiple Myeloma

“…Some of the 1q21 genes, such as IL6R [ 7 ], ILF2 [ 8 ], MCL-1 [ 9 ], ADAR1 [ 10 ], and CKS1B [ 11 ], were investigated and considered potential drivers of MM development and progression. However, many other candidate genes in this region should also be considered for their role in the pathogenesis, progression, or prognosis of myeloma [ 12 ].…”