Appraising myc involvement in high risk myeloma

Multiple myeloma (MM) is characterized by signifi cant heterogeneity in terms of presentation of the disease and eventual patient outcome. Th is heterogeneity is linked to the pathobiology of the malignant plasma cell clone. According to current knowledge of the biology of this malignancy, a period of slowly proliferative disease, monoclonal gammopathy of undetermined signifi cance (MGUS), precedes the development of symptomatic myeloma, for a few or several years. Th e transition from MGUS to asymptomatic and then symptomatic myeloma is the result of accumulation of genetic alterations in inherently genetically unstable tumor cells [1]. Several genetic alterations have been implicated in the pathogenesis of MM, with n two main pathways involving either hyperdiploidy or specifi c translocations of the immunoglobulin heavy chain (IgH) loci in chromosome 14 [2]. It has been recognized that alterations of chromosome 8 involving the c-myc locus constitute an additional event that is associated with a more aggressive transformation of MM. However, this is considered a late event, occurring in patients with very advanced disease, and is commonly encountered in human myeloma cell lines. Other genetic changes such as loss of 17p are also associated with a more aggressive course and short remission duration. Th us, the presence of genetic abnormalities such as t(4;14) and del17p are associated with poor survival, while others such as t(11;14) have a neutral prognostic eff ect. Hyperdiploidy is associated with a more favorable outcome compared with non-hyperdiploid karyotypes. Additional cytogenetic abnormalities such as add1q21, del1p, t(14;16) and t(14;20) have also been implicated as high risk markers, but their independent impact has not yet been established [3]. Until recently, and despite the fact that overexpression of myc is associated with a more aggressive phenotype, the presence of myc alterations was not routinely assessed in newly diagnosed patients, and their prognostic signifi cance has not been studied in MM. However, recent evidence indicates that c-myc overexpression may be an earlier and more frequent event in newly diagnosed patients with MM than initially believed. Walker et al . used DNA capture and an extensive parallel sequencing approach in 104 newly diagnosed patients with myeloma and identifi ed 8q24 breakpoints in 21 (20%) of these samples, with partner loci including IGH, IGK and IGL, XBP1, FAM46C, CCND1 and KRAS. Th ese translocations were associated with increased expression of MYC, and decreased progression-free and overall survival [4]. Aff er et al . identifi ed MYC rearrangements in close to 50% of cases of MM, including smoldering MM. Th ese rearrangements repositioned MYC near a limited number of genes associated with conventional enhancers, but mostly with super-enhancers (e.g. IGH, IGL, IGK, NSMCE2, TXNDC5, FAM46C, FOXO3, IGJ, PRDM1), and were associated with a signifi cant increase of monoallelic MYC expression. Furthermore, MM tumors lacking a rearrangement had biallelic MYC expression at signifi cantly higher levels than in MGUS [5]. Both of the above studies used advanced technology which is not widely available. In this issue of the journal, Glitza et al . [6] retrospectively investigated the presence of myc alterations that were identifi ed with conventional karyotype and standard fl uorescence in situ hybridization (FISH). Th eir data indicate that c-myc related abnormalities are associated with a fairly poor outcome in patients with MM, and the disease in these patients presented with an aggressive phenotype: 52% of patients bearing myc abnormalities presented with plasma cell leukemia (PCL) or extramedullary involvement. Although myc overexpression is generally linked to late and advanced stages of the disease, it seems that in some patients abnormalities of chromosome 8 may occur earlier, resulting in an