An unusual H-Ras mutant isolated from a human multiple myeloma line leads to transformation and factor-independent cell growth

Crowder, C. Michael; Kopantzev, E. P.; Williams, K.M.; Lengel, Carol; Miki, Toru; Rudikoff, Stuart

doi:10.1038/sj.onc.1206180

Cited by 18 publications

(19 citation statements)

References 54 publications

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“…11 In addition, both a Ras-activating mutation and biallelic PTEN deletion have recently been described in OPM-2, the one cell line with activated FGFR3 that is insensitive to PD173074. 24 32 Studies using primary samples to directly address this issue are limited by the inability of primary MM cells to proliferate in vitro or to be maintained for the 5 to 10 days required to see effects. A clearly more meaningful model for the study of primary MM cells is the elegant SCID-hu model whereby primary MM cells may be grown in the context of a human fetal BM microenvironment.…”

Section: Discussionmentioning

confidence: 99%

“…11 In addition, both a Ras-activating mutation and biallelic PTEN deletion have recently been described in OPM-2, the one cell line with activated FGFR3 that is insensitive to PD173074. 24 These data suggest that FGFR3 inhibitors may not be of clinical benefit in the patient population with advanced disease who have acquired Ras mutations rather than activating FGFR3 mutations. On the other hand, fewer than 5% of premalignant monoclonal gammopathy of undetermined significance (MGUS) tumors have Ras mutations (T. Rasmussen, unpublished data, 2003 32 Studies using primary samples to directly address this issue are limited by the inability of primary MM cells to proliferate in vitro or to be maintained for the 5 to 10 days required to see effects.…”

mentioning

confidence: 90%

“…On the other hand, OPM2 cells have both a Ras-activating mutation and biallelic PTEN deletions. 24 Loss of PTEN has recently been shown to counteract the antitumor activity of EGFR inhibitors in various cell types. 25 The 8226, MM1, and EJM cells, which lack FGFR3 expression, displayed no decrease in viability, demonstrating that at effective concentrations, PD173074 exhibits minimal nonspecific cytotoxicity on myeloma cells ( Figure 3B).…”

Section: Inhibition Of Fgfr3 In MM Cell Lines Inhibits Growth and Is mentioning

confidence: 99%

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Inhibition of fibroblast growth factor receptor 3 induces differentiation and apoptosis in t(4;14) myeloma

Trudel

Ely

Farooqi

et al. 2004

Blood

153

124

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We have previously shown that dysregulation of fibroblast growth factor receptor 3 (FGFR3) by the t(4;14) translocation is a primary event in multiple myeloma (MM) and that activating mutations of FGFR3 are acquired in some cases. We describe here inhibition of wild-type (WT) and constitutively activated mutant IntroductionThe inhibition of the primary genetic lesion (BCR-ABL, PML-RAR␣) can induce differentiation and apoptosis in human myeloid tumors. 1,2 Transient inactivation of MYC in an MYC transgenic mouse tumor model results in tumor cell differentiation, followed by apoptosis on subsequent MYC reactivation. 3 We wondered to what extent these observations can be generalized to other human cancers and, in particular, to lymphoid malignancies. There are 3 main reasons why this has been difficult: (1) the challenge in identifying genes that participate in the primary oncogenic process, (2) the lack of specific molecular inhibitors, and (3) the need for a well-ordered model of cell differentiation.B-cell differentiation to plasma cells (PCs) provides one such model. Following isotype switch recombination centrocytic B cells differentiate into low-rate immunoglobulin (Ig)-secreting plasmablastic cells, migrate to the bone marrow (BM), and proliferate as immature plasmablasts. 4,5 Differentiation of BM plasmablastic cells into high-rate Ig-secreting PCs is the final step to long-lived PCs, the end-stage of B-cell differentiation. Multiple myeloma (MM) has typically been defined as a neoplasm of terminally differentiated PCs; however, in contrast to fully differentiated PCs that do not proliferate, myeloma cells proliferate slowly and secrete significantly lower amounts of Ig. 6,7 The t(4;14) translocation, which occurs in approximately 15% of patients with MM, appears to be mediated by errors in isotype switch recombination and results in the dysregulated expression of 2 genes, FGFR3 and MMSET. 8,9 In particular, wild-type (WT) FGFR3, which is not normally expressed by B cells or PCs, becomes ectopically expressed at very high levels (M.C., unpublished data, November 1998).WT FGFR3 induces proliferative signals in myeloma cells and appears to be weakly transforming in a hematopoietic mouse model. 10,11 The subsequent acquisition of FGFR3-activating mutations in some MM is clearly associated with disease progression and is strongly transforming in several experimental models. 11,12 The clinical impact of t(4; 14) translocations has been demonstrated in 3 large studies each reporting a marked reduction in overall survival [13][14][15] with no apparent therapeutic benefit from high-dose chemotherapy. The clinical significance of FGFR3 expression, however, remains somewhat ambiguous, because Keats and colleagues found that t(4;14) conferred a poor prognosis irrespective of FGFR3 expression. Indeed, FGFR3 is not up-regulated in all cases of t(4;14) myeloma, and it has been found that the der14 chromosome can be lost in primary samples and cell lines. 14,16,17 These results suggest that if ectopic expression of WT FG...

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Section: Discussionmentioning

confidence: 99%

“…11 In addition, both a Ras-activating mutation and biallelic PTEN deletion have recently been described in OPM-2, the one cell line with activated FGFR3 that is insensitive to PD173074. 24 These data suggest that FGFR3 inhibitors may not be of clinical benefit in the patient population with advanced disease who have acquired Ras mutations rather than activating FGFR3 mutations. On the other hand, fewer than 5% of premalignant monoclonal gammopathy of undetermined significance (MGUS) tumors have Ras mutations (T. Rasmussen, unpublished data, 2003 32 Studies using primary samples to directly address this issue are limited by the inability of primary MM cells to proliferate in vitro or to be maintained for the 5 to 10 days required to see effects.…”

mentioning

confidence: 90%

Section: Inhibition Of Fgfr3 In MM Cell Lines Inhibits Growth and Is mentioning

confidence: 99%

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Inhibition of fibroblast growth factor receptor 3 induces differentiation and apoptosis in t(4;14) myeloma

Trudel

Ely

Farooqi

et al. 2004

Blood

153

124

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“…14 The prevalence of the mutations may increase somewhat with advancing stages of the disease (129,(131)(132)(133)(134). Most mutations involve K-and N-ras at codons 12,13 and 61, but an atypical activating mutation of H-ras was identified in a fraction of cells from one HMCL (135). With rare exceptions, it appears that a mutation occurs in only one N-or K-ras allele in a single tumor cell, although there is some evidence that subpopulations of MM tumor cells within an individual can have different Ras mutations (129,130).…”

Section: Other Genetic Abnormalitiesmentioning

confidence: 99%

Genetics and Cytogenetics of Multiple Myeloma

Fonseca

Barlogie

Bataille³

et al. 2004

Cancer Research

659

565

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“…Different result was mentioned by Crowder et al (2003), there are mutation in nucleotide GTP binding on H-Ras gene MM Astuti et al cell. Rasis anti-apoptosis and pro-apoptosis through different ways.…”

Section: Resultsmentioning

confidence: 99%

Impact of Curcuma mangga Val. Rhizome Essential Oil to p53, Bcl-2, H-Ras and Caspase-9 expression of Myeloma Cell Line

et al. 2015

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Cancer is a disease, a public health problem, which is found in the world as well as in Indonesia. In general, some of cancer theraphies are ineffective, characterized by the resistance performance of cancer cell line, the exposed normal cell and by the side effects. Nowadays, studies to fi nd the specifi c and safely anti-cancer drugs were increased by the time. Several studies revealed that Curcuma mangga Val. Rhizome contains some secondary metabolites, essential or non-essential oil, which has cytotoxic activities to the cancer cells. Based on these anti-cancer potentials, this study has several aims to recognize anti-cancer selectivity and molecular mechanism by inducting apoptosis and inhibiting myeloma cell proliferation. To C. mangga Val. essential oil, immunocyto chemical test was performed to determine the expression of p53, caspase-9, Bcl-2, H-Ras protein while TUNEL test was performed to determine the number of apoptosis cells.The results of this study shown that anti-cancer molecular mechanism of C. mangga Val. essential oil to myeloma cell line was performed by increasing apoptosis; by increasing the expression of pro-apoptosis p53, caspase-9 protein and reducing protein which is increasing proliferation Bcl-2 and H-Ras.

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An unusual H-Ras mutant isolated from a human multiple myeloma line leads to transformation and factor-independent cell growth

Cited by 18 publications

References 54 publications

Inhibition of fibroblast growth factor receptor 3 induces differentiation and apoptosis in t(4;14) myeloma

Inhibition of fibroblast growth factor receptor 3 induces differentiation and apoptosis in t(4;14) myeloma

Genetics and Cytogenetics of Multiple Myeloma

Impact of Curcuma mangga Val. Rhizome Essential Oil to p53, Bcl-2, H-Ras and Caspase-9 expression of Myeloma Cell Line

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