Article

Alteration and abnormal expression of the c-myc oncogene in human multiple myeloma

Department of Hematology, University of Texas System Cancer Center, M. D. Anderson Hospital and Tumor Institute, Houston 77030.
Blood (Impact Factor: 10.43). 02/1988; 71(1):30-5.
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ABSTRACT Structural alterations of the c-myc oncogene in human Burkitt's lymphoma and mouse plasmacytoma suggest that this oncogene is involved in several B cell neoplasms. The possibility of c-myc alterations in human myeloma has not been explored, probably because the low proliferative activity characteristic of this tumor impairs the propagation of representative cell lines for the performance of adequate cytogenetic studies. This report describes alterations in the c-myc locus with concomitant elevated expression of mRNA in the tumor cells of two of 37 patients with multiple myeloma. In one case, somatic cell hybrid studies revealed that the cloned rearranged DNA was entirely derived from chromosome 8, thus indicating a novel mechanism of c-myc activation different from that in Burkitt's lymphoma. Seven other patients exhibited five- to 12-fold overexpression of c-myc RNA when compared with normal marrow cells. Elevated mRNA expression in about one fourth of our patients suggests that the c-myc oncogene has a pathogenetic role in the evolution of multiple myeloma.

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    • "Translocation of the proto-oncogene MYC into one of the immunoglobulin gene loci [IG-MYC translocation; mostly of the t(8;14)q24;q32 type] resulting in aberrant MYC expression is regarded as the dominant genetic event in the genesis of BL and about 10% of DLBCL [4]. Besides translocation, MYC can undergo oncogenic deregulation via high-level gene amplification as well as mutations in cis-regulatory elements in several cancer types (e.g., myeloma, colon carcinoma and neuroblastoma) [5], [6]. Moreover, while most BLs have deregulated c-MYC (henceforth referred to as MYC) expression as a consequence of an IG-MYC translocation, the majority of non-BLs do not carry IG-MYC translocations, but other genetic abnormalities leading to deregulated MYC expression. "
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    ABSTRACT: High level MYC expression is associated with almost all human cancers. JQ1, a chemical compound that inhibits MYC expression is therapeutically effective in preclinical animal models in midline carcinoma, and Burkitt's lymphoma (BL). Here we show that JQ1 does not inhibit MYC expression to a similar extent in all tumor cells. The BL cells showed a ∼90% decrease in MYC transcription upon treatment with JQ1, however, no corresponding reduction was seen in several non-BL cells. Molecularly, these differences appear due to requirements of Brd4, the most active version of the Positive Transcription Elongation Factor B (P-TEFb) within the Super Elongation Complex (SEC), and transcription factors such as Gdown1, and MED26 and also other unknown cell specific factors. Our study demonstrates that the regulation of high levels of MYC expression in different cancer cells is driven by unique regulatory mechanisms and that such exclusive regulatory signatures in each cancer cells could be employed for targeted therapeutics.
    PLoS ONE 01/2014; 9(1):e87003. DOI:10.1371/journal.pone.0087003 · 3.23 Impact Factor
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    • "This discordance may be due to the variability of the clinical samples. MYC deregulation is important in myeloma (Selvanayagam et al, 1988; Chng et al, 2011), and recent evidence suggested that MYC not only regulates expression of protein-coding genes directly, but also controls the expression of a large set of miRNAs (O'Donnell et al, 2005; Chang et al, 2008). In particular , MYC upregulation has been shown to directly activate the MIR17HG and MIR106A~363 clusters (O'Donnell et al, 2005), suggesting that it may play an important role in miRNA deregulation in MM. "
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    ABSTRACT: Multiple myeloma (MM) is a heterogeneous disease. International Staging System/fluorescence hybridization (ISS/FISH)-based model and gene expression profiles (GEP) are effective approaches to define clinical outcome, although yet to be improved. The discovery of a class of small non-coding RNAs (micro RNAs, miRNAs) has revealed a new level of biological complexity underlying the regulation of gene expression. In this work, 163 presenting samples from MM patients were analysed by global miRNA profiling, and distinct miRNA expression characteristics in molecular subgroups with prognostic relevance (4p16, MAF and 11q13 translocations) were identified. Furthermore we developed an "outcome classifier", based on the expression of two miRNAs (MIR17 and MIR886-5p), which is able to stratify patients into three risk groups (median OS 19·4, 40·6 and 65·3 months, P = 0·001). The miRNA-based classifier significantly improved the predictive power of the ISS/FISH approach (P = 0·0004), and was independent of GEP-derived prognostic signatures (P < 0·002). Through integrative genomics analysis, we outlined the potential biological relevance of the miRNAs included in the classifier and their putative roles in regulating a large number of genes involved in MM biology. This is the first report showing that miRNAs can be built into molecular diagnostic strategies for risk stratification in MM.
    British Journal of Haematology 05/2013; 162(3). DOI:10.1111/bjh.12394 · 4.96 Impact Factor
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    • "Promiscuous translocations involving the 14q32 site are the most common translocations detected in MM (Bergsagel et al, 1996; Chesi et al, 1996). Other abnormalities found in MM include overexpression of oncogene protein products and mutations in tumour suppressor genes, including ras (Neri et al, 1989), p53 (Gaidano et al, 1991; Preudhomme et al, 1992; Neri et al, 1993) and c-myc (Selvanayagam et al, 1988; Greil et al, 1989; Nobuyoshi et al, 1991). Although patients harbouring the t(11;14)(q13;q32) are thought to have an aggressive course, no series of patients has been described identifying the unique laboratory and clinical features. "
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    ABSTRACT: Complex cytogenetic abnormalities have been described in patients with multiple myeloma (MM). To better understand the significance of the most frequent translocation observed in MM, we studied the clinical characteristics of patients with MM and the t(11;14)(q13;q32) abnormality. A search of the cytogenetic database at the Mayo Clinic identified patients with MM and t(11;14)(q13;q32). The medical records were reviewed for the clinical characteristics of these patients. We identified 13 patients with MM and t(11;14)(q13;q32) determined by standard cytogenetic analysis; in 10 patients the abnormality was detected at the time of relapse (three with previously normal results of cytogenetic examination). At the time the translocation was detected, plasma cell (PC) leukaemia was clinically diagnosed in two patients. The median number of circulating PCs, as determined by the cytoplasmic immunofluorescence of T-cell-depleted peripheral blood mononuclear cells, was 1.1 × 109/l (mean 1.74; range 0.0017–6.26 × 109/l). On linear regression analysis there was a strong correlation between the number of circulating PCs and the number of bone marrow PCs. The median survival after demonstration of the translocation was 8.1 months. Of all patients, 10 died of disease progression and three were alive. Patients with MM who have t(11;14)(q13;q32) seem to have an aggressive clinical course, even when the abnormality is detected at the time of diagnosis, with evidence of many circulating PCs.
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