Biological characteristics of N-myc amplified neuroblastoma in patients over one year of age.
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1. A genomic amplification of N-myc of neuroblastoma was frequently observed in patients in the advanced stage of the disease, in those with the tumor originating from the suprarenal region, and in those with a histologically undifferentiated neuroblastoma. Thus, N-myc may be one of the most pertinent prognostic factors of neuroblastoma in patients over one year of age. 2. The neuroblastoma patient with 1-10 copies of N-myc responded to aggressive multidisciplinary therapy, even those over one year of age. 3. Rapid invasion and progression of the tumor was evident in children with more than 10 copies of N-myc. 4. N-myc amplification may correlate with immaturity of catecholamine metabolism of neuroblastoma.Keywords:
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Abstract Despite the improvement in clinical outcome with 13- cis -retinoic acid (13- cis RA) + anti-GD2 antibody + cytokine immunotherapy given in first response ~40% of high-risk neuroblastoma patients die of recurrent disease. MYCN genomic amplification is a biomarker of aggressive tumors in the childhood cancer neuroblastoma. MYCN expression is downregulated by 13- cis RA, a differentiating agent that is a component of neuroblastoma therapy. Although MYC amplification is rare in neuroblastoma at diagnosis, we report transcriptional activation of MYC medicated by the transcription factor OCT4, functionally replacing MYCN in 13- cis RA-resistant progressive disease neuroblastoma in large panels of patient-derived cell lines and xenograft models. We identified novel OCT4-binding sites in the MYC promoter/enhancer region that regulated MYC expression via phosphorylation by MAPKAPK2 (MK2). OCT4 phosphorylation at the S111 residue by MK2 was upstream of MYC transcriptional activation. Expression of OCT4, MK2, and c-MYC was higher in progressive disease relative to pre-therapy neuroblastomas and was associated with inferior patient survival. OCT4 or MK2 knockdown decreased c-MYC expression and restored the sensitivity to 13- cis RA. In conclusion, we demonstrated that high c-MYC expression independent of genomic amplification is associated with disease progression in neuroblastoma. MK2-mediated OCT4 transcriptional activation is a novel mechanism for activating the MYC oncogene in progressive disease neuroblastoma that provides a therapeutic target.
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Gene amplification has been found in the genome of cells growing in vivo and/or in vitro. In cell lines with acquired multidrug resistance gene amplification has been frequently detected. Moreover, extra-copies of cellular oncogenes have been located in tumor cells in vivo; particularly N-myc gene amplification was discovered in advanced stage of neuroblastoma (NB). Neuroblastoma, a tumor of neural origin, has a high incidence in children. N-myc amplification has been demonstrated in untreated patient and a positive significant correlation with the progression of the disease has been established. In this paper we report on four NB patients treated with a polychemotherapeutic protocol and showing N-myc amplification. One patient examined before and after treatment displayed a slight change in N-myc gene copy numbers. It was shown that N-myc gene amplification is not affected by drug activities and that minimal residual of cells bearing N-myc amplification may remain in the tumor mass. N-myc amplification can also cause advantageous cell growth in the presence of drugs. The implications in the pharmacologic management of NB patient showing N-myc gene amplification is discussed.
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Although N-myc amplification in neuroblastomas correlates with poor prognosis, not all neuroblastomas which fail to respond to therapy have N-myc amplification. To determine whether other modes of myc gene activation underlie progression of some neuroblastomas, 45 were analyzed for amplification of N-myc, c-myc and L-myc and 26 were studied for transcription of these oncogenes. N-myc amplification was found in 6 of 45 tumors; no tumor had amplification of c-myc or L-myc. Transcription of both N-myc and c-myc occurred in 21 of 26 neuroblastomas. No tumor without N-myc amplification had a level of N-myc expression near that of a tumor or cell line with amplification. One tumor with N-myc amplification was the only specimen with N-myc but not c-myc expression. Five samples had c-myc but not N-myc expression; all had histological features of ganglioneuroma. DNA index did not correlate with myc gene amplification or expression. It is concluded that N-myc and c-myc are commonly expressed in primary untreated neuroblastomas, but in the absence of N-myc amplification, expression of these genes does not appear to correlate with disease progression.
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Eighty-nine patients with untreated primary neuroblastomas were studied to determine the relation between the number of copies of the N-myc oncogene and survival without disease progression. Genomic amplification (3 to 300 copies) of N-myc was detected in 2 of 16 tumors in Stage II, 13 of 20 in Stage III, and 19 of 40 in Stage IV; in contrast, 8 Stage I and 5 Stage IV-S tumors all had 1 copy of the gene (P<0.01). Analysis of progression-free survival in all patients revealed that amplification of N-myc was associated with the worst prognosis (P<0.0001); the estimated progression-free survival at 18 months was 70 per cent, 30 per cent, and 5 per cent for patients whose tumors had 1, 3 to 10, or more than 10 N-myc copies, respectively. Of 16 Stage II tumors, 2 with amplification metastasized, whereas only 1 of 14 without amplification did so (P = 0.03). Stage IV tumors with amplification progressed most rapidly: nine months after diagnosis the estimated progression-free survival was 61 per cent, 47 per cent, and 0 per cent in patients whose tumors had 1, 3 to 10, or more than 10 copies, respectively (P<0.0001). These results suggest that genomic amplification of N-myc may have a key role in determining the aggressiveness of neuroblastomas. (N Engl J Med 1985; 313: 1111–6.)
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Abstract MYCN genomic amplification is one of the risk factors in neuroblastoma. 13-cis retinoic acid (13-cisRA), a differentiating agent, down-regulates MYCN protein and is part of neuroblastoma maintenance therapy. Despite the improvement in clinical outcome with 13-cisRA, anti-GD2 monoclonal antibody plus cytokine immunotherapy given in first response ~40% of high-risk neuroblastoma patients still die of recurrent disease. Although MYC genomic amplification is rare in neuroblastoma (~1%), 11% of neuroblastoma primary tumors collected at diagnosis (Dx) have high c-MYC protein suggesting that MYC transcriptional activation rather than its gene amplification drives such tumors. Here, we sought to investigate the role of MYC oncogene in progressive disease (PD) and to molecularly characterize mechanisms of MYC expression in neuroblastoma. We report transcriptional activation of MYC medicated by the OCT4 (encoded by POU5F1), functionally replacing MYCN in 13-cisRA-resistant progressive disease neuroblastoma. In large panels of neuroblastoma patient-derived cell lines (19 Dx and 16 PD) and patient-derived xenograft PDX models (8 Dx and 9 PD), we confirmed that c-MYC expression levels were higher in PD relative to Dx lines (P = 0.0005). We identified OCT4 and TCF3 as transcription factors highly expressed in neuroblastoma cells with high c-MYC. Subsequently, we confirmed two novel OCT4-binding sites (including OBS1 and OBS2) located in the MYC promoter/enhancer region: -1209 to -1140 and found that OCT4 NH2-terminal domain (NTD) and POU specific domain (POUs) are critical for MYC transcriptional activation. To identify kinases that is associated with OCT4-induced c-MYC activation, we used mass spectrometry and PhosphoMotif Finder® and identified MAPKAPK2 (MK2) as one of the upstream kinases that can bind to and directly regulate the OCT4 biological function by phosphorylation at its amino acid Ser111 residue to transcriptionally activate MYC expression. The data in 175 MYCN non-amplified high-risk primary tumors (TARGET database) showed that MAPKAPK2 positively correlated with MYC expression (P < 0.001) and overall survival was lower (P < 0.001) for patients with high MAPKAPK2. Also, OCT4, MK2, and c-MYC were higher in PD relative to Dx neuroblastomas models. Functional studies by gene knockdown of the POU5F1 or MAPKAPK2 using shRNAs showed decreased c-MYC expression, inhibition of cell proliferation, and restoring neurite outgrowth in response to 13-cisRA. In conclusion, high c-MYC independent of genomic amplification, not MYCN amplification, is associated with disease progression in neuroblastoma. The MK2-mediated OCT4 transcriptional activation is a novel mechanism for MYC activation in PD neuroblastoma and provides a potential novel therapeutic target. Citation Format: Sung Jen Wei, Thinh H. Nguyen, Dustin G. Mook, Monish R. Makena, Dattesh Verlekar, Ashly Hindle, Gloria Martinez, Shengping Yang, Hiroyuki Shimada, C. Patrick Reynolds, Min H. Kang. MYC transcription activation mediated by OCT4 as a mechanism of resistance to 13-cisRA-mediated differentiation in neuroblastoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1293.
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N-myc amplification is most frequently found in neuroblastoma from patients with stage III and IV disease. Recently a significant association between genomic amplification and poor prognosis has been demonstrated. The primary tumors studied from patients with stage IVS disease have reportedly had a single copy of N-myc, and these patients are alive without progressive disease. We report a patient with stage IVS neuroblastoma with N-myc amplification who developed widespread metastasis within 6 months of diagnosis. The same correlation between oncogene copy number and progressive disease that has been seen in those patients with stage II, III, and IV disease was seen in this patient with stage IVS neuroblastoma.
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The L‐ myc , N‐ myc and c‐ myc genes are members of the myc oncogene family. In particular, L‐ myc is novel, and amplification of L‐ tnyc is still unknown except in small cell lung carcinoma. We examined L‐ myc amplification in 30 human neuroblastomas using Southern blot hybridization, and found that the L‐ myc gene was amplified approximately 5‐fold in GOTO, a human neuroblastoma cell line. The N‐ myc gene was also amplified approximately 60‐fold and furthermore, over‐expression of L‐ myc and N‐ myc genes was observed in this cell line. In this report, we describe the coampliflcation of the myc gene family in the GOTO neuroblastoma cell line.
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