Frequent Dysregulation of the c-maf Proto-Oncogene at 16q23 by Translocation to an Ig Locus in Multiple Myeloma

Blood ◽  
1998 ◽  
Vol 91 (12) ◽  
pp. 4457-4463 ◽  
Author(s):  
Marta Chesi ◽  
P. Leif Bergsagel ◽  
Oluwatoyin O. Shonukan ◽  
Maria Luisa Martelli ◽  
Leslie A. Brents ◽  
...  

Dysregulation of oncogenes by translocation to an IgH (14q32) or IgL (κ, 2p11 or λ, 22q11) locus is a frequent event in the pathogenesis of B-cell tumors. Translocations involving an IgH locus and a diverse but nonrandom array of chromosomal loci occur in most multiple myeloma (MM) tumors even though the translocations often are not detected by conventional cytogenetic analysis. In a continuing analysis of translocations in 21 MM lines, we show that the novel, karyotypically silent t(14;16)(q32.3;q23) translocation is present in 5 MM lines, with cloned breakpoints from 4 lines dispersed over an approximately 500-kb region centromeric to the c-maf proto-oncogene at 16q23. Another line has a t(16;22)(q23;q11), with the breakpoint telomeric to c-maf, so that the translocation breakpoints in these 6 lines bracket c-maf. Only these 6 lines overexpress c-mafmRNA. As predicted for dysregulation of c-maf by translocation, there is selective expression of one c-maf allele in 2 informative lines with translocations. This is the first human tumor in which the basic zipper c-maf transcription factor is shown to function as an oncogene.

Blood ◽  
1998 ◽  
Vol 91 (12) ◽  
pp. 4457-4463 ◽  
Author(s):  
Marta Chesi ◽  
P. Leif Bergsagel ◽  
Oluwatoyin O. Shonukan ◽  
Maria Luisa Martelli ◽  
Leslie A. Brents ◽  
...  

Abstract Dysregulation of oncogenes by translocation to an IgH (14q32) or IgL (κ, 2p11 or λ, 22q11) locus is a frequent event in the pathogenesis of B-cell tumors. Translocations involving an IgH locus and a diverse but nonrandom array of chromosomal loci occur in most multiple myeloma (MM) tumors even though the translocations often are not detected by conventional cytogenetic analysis. In a continuing analysis of translocations in 21 MM lines, we show that the novel, karyotypically silent t(14;16)(q32.3;q23) translocation is present in 5 MM lines, with cloned breakpoints from 4 lines dispersed over an approximately 500-kb region centromeric to the c-maf proto-oncogene at 16q23. Another line has a t(16;22)(q23;q11), with the breakpoint telomeric to c-maf, so that the translocation breakpoints in these 6 lines bracket c-maf. Only these 6 lines overexpress c-mafmRNA. As predicted for dysregulation of c-maf by translocation, there is selective expression of one c-maf allele in 2 informative lines with translocations. This is the first human tumor in which the basic zipper c-maf transcription factor is shown to function as an oncogene.


Oncogene ◽  
2010 ◽  
Vol 30 (11) ◽  
pp. 1329-1340 ◽  
Author(s):  
L Yang ◽  
H Wang ◽  
S M Kornblau ◽  
D A Graber ◽  
N Zhang ◽  
...  

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 171-171
Author(s):  
Zhigang Xie ◽  
Chonglei Bi ◽  
Jing Yuan Chooi ◽  
Zit Liang Chan ◽  
Nurulhuda Mustafa ◽  
...  

Abstract Multiple myeloma (MM) is a genetically complex disease that is becoming more common in today’s ageing population. Approximately 50% of MM harbour recurrent translocations involving the immunoglobulin heavy chain (IgH) locus on chromosome 14q32. The translocation t(4;14)(p16;q32) is one of the most common translocation in MM and is associated with very poor prognosis. The multiple myeloma SET domain (MMSET), involved in the fusion to the IgH locus in t(4;14) MM, is universally overexpressed and has been suggested to play an important role in tumorigenicity in t(4;14) MM. In order to identify downstream functional targets of MMSET, we knocked down MMSET expression with shRNAs in KMS11, a t(4;14) MM cell line, and identified differentially expressed genes by gene expression microarray analysis. The results identified 321 down-regulated and 375 up-regulated genes upon MMSET knockdown. Of interest, the knockdown reduced the transcription levels of the transcription factor IRF4 (interferon regulatory factor 4), which has been shown recently to be required for myeloma cell survival. Quantitative PCR (QPCR) analysis confirmed the transcription levels of IRF4 were reduced upon MMSET knockdown in t(4;14) MM cells (KMS11, KMS18, KMS28BM). Western-blots analysis indicated MMSET knockdown reduced protein levels of IRF4, c-Myc and PARP, and IRF4 knockdown could also reduce protein levels of c-Myc and PARP. Flow cytometric analysis indicated silencing of MMSET or IRF4 could induce apoptosis in t(4;14) MM cells. QPCR and Western-blot analysis revealed that ectopic expression of MMSET could increase IRF4 expression in KMS11 cells. Using chromatin immunoprecipitation (ChIP), both MMSET and NFκB can bind to the promoter region of IRF4, and the binding region of MMSET is located 1 kb upstream of that of NFκB. Furthermore, endogenous NFκB p65 could be coprecipitated by anti-MMSET antibody, indicating the association of MMSET and NFκB. These data suggest that MMSET may be a coactivator for NFkB in the regulation of IRF4 expression. Luciferase reporter assays in KMS11 cells showed the activity of IRF4 promoters were decreased significantly upon MMSET knockdown, suggesting MMSET is an important functional element for IRF4 promoter. Cell proliferation assays and apoptosis analysis showed that silencing of MMSET could sensitize t(4;14) MM cells to Bortezomib and Melphalan killing. In myeloma xenograft, combined MMSET silencing with Melphalan or Bortezomib resulted in significantly greater inhibition of t(4;14) MM tumorigeness than treatments with either drugs alone. Importantly, we found both of Melphalan and Bortezomib could also reduce protein levels of MMSET and IRF4. QPCR analysis indicated that they inhibited MMSET and IRF4 expression through transcription control. These results might partly explain the additive mechanism of combination of MMSET knockdown and Melphalan or Bortezomib. Overall, our data indicated MMSET is involved in the regulatory network of IRF4 that is critical for t(4:14) MM cell survival, and its silence potentiates the effect of antimyeloma agents in vitro and in vivo. Disclosures No relevant conflicts of interest to declare.


Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1556-1556 ◽  
Author(s):  
Jonathan J. Keats ◽  
Erin Strachan ◽  
Andrew R. Belch ◽  
Linda M. Pilarski

Abstract Translocations involving the IgH locus are one of the most common genetic abnormalities observed in multiple myeloma (MM). Unlike several hematological malignancies, MM IgH translocations involve multiple partner chromosomes. Although IgH translocations are not unique to MM, the molecular anatomy of the translocations appears to be different from that observed in most B-cell malignancies. In general, the breakpoints occur within the switch regions of the IgH locus and the translocations appear to result from illegitimate class switch recombination (CSR) events. Previous analysis of the breakpoint junctions from t(4;14) samples suggested that the majority of these translocations result from illegitimate CSR events. These events were characterized by der(4) breakpoints containing Smu-chromosome 4 junctions and der(14) breakpoints with chromosome 4-downstream switch region junctions. However, not all t(4;14) breakpoints fit this “classical” model, as some derivative chromosomes were observed with hybrid switch regions. Unfortunately, the mechanism that generates these hybrid switch regions has been unclear. In general, only a single derivative was cloned from each patient or cell line. In the one case reported elsewhere in which both derivatives were cloned, the mechanism did not appear to be linked to the CSR process and thus represented a “non-classical” translocation. The poor prognostic impact of t(4;14) myeloma has been well established by several groups, including our own. In an attempt to identify recurrent breakpoint sites and to identify the potential mechanism(s) leading to t(4;14) translocations, we cloned the breakpoint junctions of both derivative chromosomes from 4 cell lines and 5 patients with MB4-2 and MB4-3 breakpoints. Furthermore, we cloned der(4) breakpoints from 4 additional patients, three of which are FGFR3 non-expressers for which we could not detect a der(14) breakpoint using our PCR based strategy. We defined the t(4;14) breakpoint region as encompassing 64.5 kb of chromosome 4, flanked by LETM1 exon 3 and MMSET exon 5, based on combining the previously published breakpoints with our newly cloned and sequenced breakpoints. Current dogma suggests that t(4;14) translocation events are randomly distributed throughout the defined breakpoint region, but this idea is not supported by our sequencing data. We identified two hotspots, which contain breakpoints from 9 of the 27 patients or cell lines with at least one cloned derivative. Interestingly, these regions only represent 1 kb of the entire breakpoint region. Therefore 33% of the cloned breakpoints exist within only 1.5% of the total breakpoint region. Moreover, for the 13 MM samples for which both derivatives are cloned, although 6/13 (46%) fit the classical model of CSR mediated switch translocations, surprisingly, 7/13 (54%) appear to be non-classical translocations. The non-classical translocations are defined by little to no loss of sequence from the involved switch region and the presence of a hybrid switch region on one of the two derivative chromosomes. Importantly, the non-classical translocations may not involve B-cell specific mechanisms and could potentially occur before or after a successful CSR event. Therefore, the classical illegitimate CSR event model can explain only half of the t (4; 14) breakpoints cloned to date.


2015 ◽  
Vol 15 ◽  
pp. e222
Author(s):  
T. Paíno ◽  
A. García-Gómez ◽  
L. González-Méndez ◽  
L. San-Segundo ◽  
S. Hernández-García ◽  
...  

2021 ◽  
Vol 21 ◽  
pp. S442
Author(s):  
Claudio Cerchione ◽  
Lucio Catalano ◽  
Davide Nappi ◽  
Fabrizio Pane ◽  
Giovanni Martinelli

2022 ◽  
Vol 162 ◽  
pp. 105349
Author(s):  
Fabiola Bello ◽  
Esther Orozco ◽  
Claudia G. Benítez-Cardoza ◽  
Absalom Zamorano-Carrillo ◽  
César A. Reyes-López ◽  
...  

2018 ◽  
Vol 50 (6) ◽  
pp. 2390-2405 ◽  
Author(s):  
Shuping Wei ◽  
Jingjing Zhang ◽  
Biao Han ◽  
Jianxun Liu ◽  
Xiaohui Xiang ◽  
...  

Background/Aims: Phenotypic switching of vascular smooth muscle cells (VSMC) plays a vital role in the development of vascular diseases. All-trans retinoic acid (ATRA) is known to regulate VSMC phenotypes. However, the underlying mechanisms remain completely unknown. Here, we have investigated the probable roles and underlying mechanisms of the novel C2H2 zinc finger transcription factor ZFP580 on ATRA-induced VSMC differentiation. Methods: VSMCs were isolated, cultured, and identified. VSMCs were infected with an adenovirus encoding ZFP580 or Ad-siRNA to silence ZFP580. The expression levels of ZFP580, SMα-actin, SM22α, SMemb, RARα, RARβ, and RARγ were assayed by Q-PCR and western blot. A rat carotid artery injury model and morphometric analysis of intimal thickening were also used in this study. Results: ATRA caused a significant reduction of VSMC proliferation and migration in a doseand time-dependent manner. Moreover, it promoted VSMC differentiation by enhancing expression of differentiation markers and reducing expression of dedifferentiation markers. This ATRA activity was accompanied by up-regulation of ZFP580, with concomitant increases in RARα expression. In contrast, silencing of the RARα gene or inhibiting RARα with its antagonist Ro41-5253 abrogated the ATRA-induced ZFP580 expression. Furthermore, ATRA binding to RARα induced ZFP580 expression via the PI3K/Akt and ERK pathways. Adenovirusmediated overexpression of ZFP580 promoted VSMC differentiation by enhancing expression of SM22α and SMα-actin and reducing expression of SMemb. In contrast, silencing ZFP580 dramatically reduced the expression of differentiation markers and increased expression of dedifferentiation markers. The classic rat carotid artery balloon injury model demonstrated that ZFP580 inhibited proliferation and intimal hyperplasia in vivo. Conclusion: The novel zinc finger transcription factor ZFP580 facilitates ATRA-induced VSMC differentiation by the RARα-mediated PI3K/Akt and ERK signaling pathways. This might represent a novel mechanism of regulation of ZFP580 by ATRA and RARα, which is critical for understanding the biological functions of retinoids during VSMC phenotypic modulation.


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