MYOG

Gene Summary

Gene:MYOG; myogenin (myogenic factor 4)
Aliases: MYF4, myf-4, bHLHc3
Location:1q31-q41
Summary:Myogenin is a muscle-specific transcription factor that can induce myogenesis in a variety of cell types in tissue culture. It is a member of a large family of proteins related by sequence homology, the helix-loop-helix (HLH) proteins. It is essential for the development of functional skeletal muscle. [provided by RefSeq, Jul 2008]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:myogenin
HPRD
Source:NCBIAccessed: 25 June, 2015

Ontology:

What does this gene/protein do?
Show (18)

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 25 June 2015 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Messenger RNA
  • DNA Primers
  • Receptors, Cholinergic
  • Translocation
  • Muscles
  • Cancer Gene Expression Regulation
  • Myogenin
  • Cell Line
  • Immunohistochemistry
  • Rhabdomyosarcoma
  • Muscle Proteins
  • DNA-Binding Proteins
  • Paired Box Transcription Factors
  • Wilms Tumour
  • Soft Tissue Sarcoma
  • Childhood Cancer
  • MyoD Protein
  • X Chromosome
  • Transcription Factors
  • Alveolar Rhabdomyosarcoma
  • Forkhead Transcription Factors
  • Oncogene Fusion Proteins
  • Adolescents
  • Muscle, Skeletal
  • p53 Protein
  • Base Sequence
  • Tissue Array Analysis
  • Tumor Markers
  • Rhabdomyosarcoma, Embryonal
  • Nuclear Proteins
  • RTPCR
  • Tumor Suppressor Proteins
  • PAX7
  • Myogenic Regulatory Factors
  • Chromosome 1
  • Infant
  • Monoclonal Antibodies
  • Myosin Heavy Chains
  • MYOG
  • RT-PCR
  • Cell Differentiation
Tag cloud generated 25 June, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: MYOG (cancer-related)

Berkholz J, Kuzyniak W, Hoepfner M, Munz B
Overexpression of the skNAC gene in human rhabdomyosarcoma cells enhances their differentiation potential and inhibits tumor cell growth and spreading.
Clin Exp Metastasis. 2014; 31(8):869-79 [PubMed] Related Publications
Skeletal and heart muscle-specific variant of the alpha subunit of nascent polypeptide complex (skNAC) is exclusively present in striated muscle cells. During skeletal muscle cell differentiation, skNAC expression is strongly induced, suggesting that the protein might be a regulator of the differentiation process. Rhabdomyosarcoma is a tumor of skeletal muscle origin. Since there is a strong inverse correlation between rhabdomyosarcoma cell differentiation status and metastatic potential, we analyzed skNAC expression patterns in a set of rhabdomyosarcoma cell lines: Whereas RD/12 and RD/18 cells showed a marked induction of skNAC gene expression upon the induction of differentiation-similarly as the one seen in nontransformed myoblasts-skNAC was not induced in CCA or Rh30 cells. Overexpressing skNAC in CCA and Rh30 cells led to a reduction in cell cycle progression and cell proliferation accompanied by an upregulation of specific myogenic differentiation markers, such as Myogenin or Myosin Heavy Chain. Furthermore, in contrast to vector-transfected controls, a high percentage of the cells formed long, Myosin Heavy Chain-positive, multinucleate myotubes. Consistently, soft agar assays revealed a drop in the metastatic potential of skNAC-overexpressing cells. Taken together, these data indicate that reconstitution of skNAC expression can enhance the differentiation potential of rhabdomyosarcoma cells and reduces their metastatic potential, a finding which might have important therapeutic implications.

Shimada C, Todo Y, Okamoto K, et al.
Central type primitive neuroectodermal tumor/neuroblastoma of the uterus: a case report.
J Obstet Gynaecol Res. 2014; 40(10):2118-22 [PubMed] Related Publications
We encountered a 63-year-old woman who had a uterine tumor with peritoneal dissemination and para-aortic lymph node metastasis. Microscopic specimens of the tumor showed a small blue round-cell tumor. Immunohistochemistry showed cells to be negative for cytokeratin AE1/3, desmin, myogenin, CD10, CD34, and CD99, focal positive for vimentin, and positive for muscle-specific actin (HHF-35), neurofilament, synaptophysin and CD56. Fluorescence in situ hybridization revealed no split signal showing Ewing sarcoma breakpoint region 1 gene translocation. Deletion of 1p36 was identified in 30% of the tumor cells. These findings are thought to be equivalent to central type primitive neuroectodermal tumors/neuroblastoma. Cytoreductive debulking surgery followed by chemotherapy, including cyclophosphamide, vincristine and adriamycin, resulted in complete remission. She has no evidence of disease at 24 months after surgery.

Chiappalupi S, Riuzzi F, Fulle S, et al.
Defective RAGE activity in embryonal rhabdomyosarcoma cells results in high PAX7 levels that sustain migration and invasiveness.
Carcinogenesis. 2014; 35(10):2382-92 [PubMed] Related Publications
Rhabdomyosarcoma is a muscle-derived malignant tumor mainly affecting children. The most frequent variant, embryonal rhabdomyosarcoma (ERMS) is characterized by overexpression of the transcription factor, PAX7 which prevents ERMS cells from exiting the cell cycle and terminally differentiating. However, a role for PAX7 in the invasive properties of ERMS cells has not been investigated in detail thus far. Here we show that ectopic expression of receptor for advanced glycation end-products (RAGE) in human ERMS cells results in the activation of a RAGE/myogenin axis which downregulates PAX7 by transcriptional and post-translational mechanisms, as in normal myoblasts, and reduces metastasis formation. High PAX7 sustains migration and invasiveness in ERMS cells by upregulating EPHA3 and EFNA1 and downregulating NCAM1 thus decreasing the neural cell adhesion molecule (NCAM)/polysialylated-NCAM ratio. Microarray gene expression analysis shows that compared with the RAGE(-ve) TE671/WT cells and similarly to primary human myoblasts, TE671/RAGE cells show upregulation of genes involved in muscle differentiation and cell adhesion, and downregulation of cell migration related and major histocompatibility complex class I genes. Our data reveal a link between PAX7 and metastasis occurrence in ERMSs, and support a role for the RAGE/myogenin axis in metastasis suppression. Thus, low RAGE expression in ERMS primary tumors may be predictive of metastatic behavior.

Rudzinski ER, Anderson JR, Lyden ER, et al.
Myogenin, AP2β, NOS-1, and HMGA2 are surrogate markers of fusion status in rhabdomyosarcoma: a report from the soft tissue sarcoma committee of the children's oncology group.
Am J Surg Pathol. 2014; 38(5):654-9 [PubMed] Free Access to Full Article Related Publications
Pediatric rhabdomyosarcoma (RMS) is traditionally classified on the basis of the histologic appearance into alveolar (ARMS) and embryonal (ERMS) subtypes. The majority of ARMS contain a PAX3-FOXO1 or PAX7-FOXO1 gene fusion, but about 20% do not. Intergroup Rhabdomyosarcoma Study stage-matched and group-matched ARMS typically behaves more aggressively than ERMS, but recent studies have shown that it is, in fact, the fusion status that drives the outcome for RMS. Gene expression microarray data indicate that several genes discriminate between fusion-positive and fusion-negative RMS with high specificity. Using tissue microarrays containing a series of both ARMS and ERMS, we identified a panel of 4 immunohistochemical markers-myogenin, AP2β, NOS-1, and HMGA2-which can be used as surrogate markers of fusion status in RMS. These antibodies provide an alternative to molecular methods for identification of fusion-positive RMS, particularly in cases in which there is scant or poor-quality material. In addition, these antibodies may be useful in fusion-negative ARMS as an indicator that a variant gene fusion may be present.

Ciarapica R, Carcarino E, Adesso L, et al.
Pharmacological inhibition of EZH2 as a promising differentiation therapy in embryonal RMS.
BMC Cancer. 2014; 14:139 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Embryonal Rhabdomyosarcoma (RMS) is a pediatric soft-tissue sarcoma derived from myogenic precursors that is characterized by a good prognosis in patients with localized disease. Conversely, metastatic tumors often relapse, leading to a dismal outcome. The histone methyltransferase EZH2 epigenetically suppresses skeletal muscle differentiation by repressing the transcription of myogenic genes. Moreover, de-regulated EZH2 expression has been extensively implied in human cancers. We have previously shown that EZH2 is aberrantly over-expressed in RMS primary tumors and cell lines. Moreover, it has been recently reported that EZH2 silencing in RD cells, a recurrence-derived embryonal RMS cell line, favors myofiber-like structures formation in a pro-differentiation context. Here we evaluate whether similar effects can be obtained also in the presence of growth factor-supplemented medium (GM), that mimics a pro-proliferative microenvironment, and by pharmacological targeting of EZH2 in RD cells and in RD tumor xenografts.
METHODS: Embryonal RMS RD cells were cultured in GM and silenced for EZH2 or treated with either the S-adenosylhomocysteine hydrolase inhibitor 3-deazaneplanocin A (DZNep) that induces EZH2 degradation, or with a new class of catalytic EZH2 inhibitors, MC1948 and MC1945, which block the catalytic activity of EZH2. RD cell proliferation and myogenic differentiation were evaluated both in vitro and in vivo.
RESULTS: Here we show that EZH2 protein was abnormally expressed in 19 out of 19 (100%) embryonal RMS primary tumors and cell lines compared to their normal counterparts. Genetic down-regulation of EZH2 by silencing in GM condition reduced RD cell proliferation up-regulating p21Cip1. It also resulted in myogenic-like differentiation testified by the up-regulation of myogenic markers Myogenin, MCK and MHC. These effects were reverted by enforced over-expression of a murine Ezh2, highlighting an EZH2-specific effect. Pharmacological inhibition of EZH2 using either DZNep or MC inhibitors phenocopied the genetic knockdown of EZH2 preventing cell proliferation and restoring myogenic differentiation both in vitro and in vivo.
CONCLUSIONS: These results provide evidence that EZH2 function can be counteracted by pharmacological inhibition in embryonal RMS blocking proliferation even in a pro-proliferative context. They also suggest that this approach could be exploited as a differentiation therapy in adjuvant therapeutic intervention for embryonal RMS.

Riuzzi F, Sorci G, Sagheddu R, et al.
RAGE signaling deficiency in rhabdomyosarcoma cells causes upregulation of PAX7 and uncontrolled proliferation.
J Cell Sci. 2014; 127(Pt 8):1699-711 [PubMed] Related Publications
Embryonal rhabdomyosarcomas (ERMSs) show elevated levels of PAX7, a transcription factor that marks quiescent adult muscle stem (satellite) cells and is important for proliferation and survival of activated satellite cells and whose timely repression is required for myogenic differentiation. However, the mechanism of PAX7 accumulation in ERMSs and whether high PAX7 causes uncontrolled proliferation in ERMS remains to be elucidated. The receptor for advanced glycation end-products (RAGE, encoded by AGER) transduces a myogenic and anti-proliferative signal in myoblasts, and stable transfection of the ERMS cell line TE671, which does not express RAGE, with AGER results in reduced proliferation and formation of tumor masses in vivo, and enhanced apoptosis and myogenic differentiation. Herein, we show that RAGE expression is low or absent in human ERMSs. We also show that in ERMS cells (1) PAX7 accumulates owing to absent or low RAGE signaling; (2) elevated PAX7 levels reduce RAGE expression and levels of MyoD and myogenin, muscle-specific transcription factors required for myoblast proliferation arrest and differentiation, respectively; (3) PAX7 supports myoblast proliferation by reducing the levels of MyoD, primarily by promoting its degradation; and (4), when ectopically expressed in ERMS cells, that RAGE upregulates myogenin which upregulates MyoD and downregulates PAX7, with consequent inhibition of proliferation and stimulation of differentiation. Thus, failure to express RAGE and, hence, MyoD and myogenin above a critical level in ERMS cells might result in deregulated PAX7 expression leading to uncontrolled proliferation and, potentially, to rhabdomyosarcomagenesis.

Zhu B, Zhang M, Byrum SD, et al.
TBX2 blocks myogenesis and promotes proliferation in rhabdomyosarcoma cells.
Int J Cancer. 2014; 135(4):785-97 [PubMed] Article available free on PMC after 15/08/2015 Related Publications
Rhabdomyosarcomas (RMSs) are the most frequent soft tissue sarcomas in children that share many features of developing skeletal muscle. We have discovered that a T-box family member, TBX2, is highly upregulated in tumor cells of both major RMS subtypes. TBX2 is a repressor that is often overexpressed in cancer cells and is thought to function in bypassing cell growth control, including repression of p14 and p21. The cell cycle regulator p21 is required for the terminal differentiation of skeletal muscle cells and is silenced in RMS cells. We have found that TBX2 interacts with the myogenic regulatory factors MyoD and myogenin and inhibits the activity of these factors. TBX2 is expressed in primary myoblasts and C2C12 cells, but is strongly downregulated upon differentiation. TBX2 recruits the histone deacetylase HDAC1 and is a potent inhibitor of the expression of muscle-specific genes and the cell cycle regulators, p21 and p14. TBX2 promotes the proliferation of RMS cells and either depletions of TBX2 or dominant negative TBX2 upregulate p21- and muscle-specific genes. Significantly, depletion or interference with TBX2 completely inhibits tumor growth in a xenograft assay, highlighting the oncogenic role of TBX2 in RMS cells. Thus, the data demonstrate that elevated expression of TBX2 contributes to the pathology of RMS cells by promoting proliferation and repressing differentiation-specific gene expression. These results show that deregulated TBX2 serves as an oncogene in RMS, suggesting that TBX2 may serve as a new diagnostic marker or therapeutic target for RMS tumors.

Win KT, Lee MY, Tan TD, et al.
Nasopharyngeal alveolar rhabdomyosarcoma expressing CD56: a mimicker of extranodal natural killer/T-cell lymphoma.
Int J Clin Exp Pathol. 2014; 7(1):451-5 [PubMed] Article available free on PMC after 15/08/2015 Related Publications
Alveolar rhabdomyosarcoma (ARMS) is remarkably rare in adults older than 45 years. Histologically, the tumor is composed of blue round cells with frequent expression of CD56 in addition to myogenic markers. Recent studies of ARMS have shown two specific recurrent translocations: PAX3-FKHR [t(2;13)(q35;q14)] or PAX7-FKHR [t(1;13)(p36;q14)]. Extranodal natural killer (NK)/T-cell lymphoma (ENKTL) occurs most frequently in the upper aerodigestive tract with a male preference in East Asia and Central and South Americas with neoplastic cells frequently expressing CD56. We report a 53-year-old Taiwanese man presenting with a nasopharyngeal mass, cervical lymphadenopathy, and multiple bone metastases. Histologically, the nasopharyngeal biopsy revealed diffuse sheets of small blue round tumor cells without obvious alveolar pattern, angioinvasion or tumor necrosis. An initial erroneous diagnosis of ENKTL was made due to CD56 expression using fresh tumor tissue with flow cytometric analysis and the patient was treated accordingly. Retrospective study showed that the tumor cells expressed CD56, desmin, and myogenin. Fluorescence in situ hybridization revealed that the tumor cells were positive for FKHR gene rearrangement, confirming the diagnosis of ARMS. Our case illustrates that a diagnosis of ENKTL based solely on CD56 expression can be misleading for a nasopharyngeal small blue round cell tumor. ARMS should be included as a differential diagnosis, and a correct diagnosis can be reached only after a high index of suspicion and a thorough histological examination with the aid of ancillary studies.

Zin A, Bertorelle R, Dall'Igna P, et al.
Epithelioid rhabdomyosarcoma: a clinicopathologic and molecular study.
Am J Surg Pathol. 2014; 38(2):273-8 [PubMed] Related Publications
Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma and is mostly represented by the embryonal (ERMS) and alveolar (ARMS) histotypes. Whereas ERMS shows variable genetic alterations including TP53, RB1, and RAS mutations, ARMS carries a gene fusion between PAX3 or PAX7 and FOXO1. Epithelioid RMS is a morphologic variant of RMS recently described in adults. Five cases of epithelioid RMS were identified after histologic review of 85 cases of ARMS enrolled in Italian therapeutic protocols. Immunostaining analyses (muscle-specific actin, desmin, myogenin, AP-2β, EMA, cytokeratins, INI-1) and reverse transcription polymerase chain reaction assays to detect MyoD1, myogenin, and PAX3/7-FOXO1 transcripts were performed. In 4 cases DNA sequencing of TP53 was performed; and RB1 allelic imbalance and homozygous deletion were analyzed by quantitative real-time polymerase chain reaction. Histologically, epithelioid RMS displayed sheets of large cells without rhabdomyoblastic differentiation or anaplasia in 3 and prominent rhabdoid cells in 2; necrosis was evident in 4, often with a geographic pattern. Immunostainings for INI, desmin, myogenin (scattered cells in 4, diffuse in 1) were positive in all; EMA and MNF116 were positive in 2; AP-2β was negative. PAX3/7-FOXO1 transcripts were absent. In all cases RB1 was wild type, and a TP53 mutation at R273H codon was found in 1. All patients are in complete remission, with a median follow-up of 6 years. Epithelioid RMS may occur in children and is probably related to ERMS, as suggested by lack of fusion transcripts, weak staining for myogenin, negative AP-2β, evidence of TP53 mutation (although only in 1 case), and a favorable clinical course.

Sabater-Marco V, Zapater Latorre E, Martorell Cebollada M
Postradiation cutaneous pleomorphic rhabdomyosarcoma with extracellular collagen deposits reminiscent of so-called amianthoid fibers.
J Cutan Pathol. 2014; 41(3):316-21 [PubMed] Related Publications
Rhabdomyosarcoma is a malignant mesenchymal neoplasm that rarely presents as primary skin tumor. So-called amianthoid fibers are hyalinized collagen mats that have been described in myofibroblastic tumors but not in rhabdomyosarcoma. A 65-year-old male developed a submandibular nodule 9 years after an oral squamous cell carcinoma, which had been treated with chemotherapy and radiotherapy. Histological examination of the nodule revealed a pleomorphic rhabdomyosarcoma with extracellular collagen deposits reminiscent of so-called amianthoid fibers. By immunohistochemistry, the tumor cells were positive for vimentin, desmin, smooth muscle actin (SMA), muscle-specific actin (MSA), CD10, CD56, CD99, β-catenin and D2-40. However, only 15-20% of the tumor cells were positive for myoglobin, MyoD1 and myf-4/myogenin. We describe first so-called amianthoid fibers harboring blood capillaries in a rhabdomyosarcoma, suggesting that they are rigid collagen structures that lead to tumor vascularization. The low expression for myogenic regulatory proteins and strong expression for other markers may be misleading and do not contribute to the diagnosis of rhabdomyosarcoma.

Zhang M, Truscott J, Davie J
Loss of MEF2D expression inhibits differentiation and contributes to oncogenesis in rhabdomyosarcoma cells.
Mol Cancer. 2013; 12(1):150 [PubMed] Article available free on PMC after 15/08/2015 Related Publications
BACKGROUND: Rhabdomyosarcoma (RMS) is a highly malignant pediatric cancer that is the most common form of soft tissue tumors in children. RMS cells have many features of skeletal muscle cells, yet do not differentiate. Thus, our studies have focused on the defects present in these cells that block myogenesis.
METHODS: Protein and RNA analysis identified the loss of MEF2D in RMS cells. MEF2D was expressed in RD and RH30 cells by transient transfection and selection of stable cell lines, respectively, to demonstrate the rescue of muscle differentiation observed. A combination of techniques such as proliferation assays, scratch assays and soft agar assays were used with RH30 cells expressing MEF2D to demonstrate the loss of oncogenic growth in vitro and xenograft assays were used to confirm the loss of tumor growth in vivo.
RESULTS: Here, we show that one member of the MEF2 family of proteins required for normal myogenesis, MEF2D, is largely absent in RMS cell lines representing both major subtypes of RMS as well as primary cells derived from an embryonal RMS model. We show that the down regulation of MEF2D is a major cause for the failure of RMS cells to differentiate. We find that MyoD and myogenin are bound with their dimerization partner, the E proteins, to the promoters of muscle specific genes in RMS cells. However, we cannot detect MEF2D binding at any promoter tested. We find that exogenous MEF2D expression can activate muscle specific luciferase constructs, up regulate p21 expression and increase muscle specific gene expression including the expression of myosin heavy chain, a marker for skeletal muscle differentiation. Restoring expression of MEF2D also inhibits proliferation, cell motility and anchorage independent growth in vitro. We have confirmed the inhibition of tumorigenicity by MEF2D in a tumor xenograft model, with a complete regression of tumor growth.
CONCLUSIONS: Our data indicate that the oncogenic properties of RMS cells can be partially attributed to the loss of MEF2D expression and that restoration of MEF2D may represent a useful therapeutic strategy to decrease tumorigenicity.

Szuhai K, de Jong D, Leung WY, et al.
Transactivating mutation of the MYOD1 gene is a frequent event in adult spindle cell rhabdomyosarcoma.
J Pathol. 2014; 232(3):300-7 [PubMed] Related Publications
Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma in children and adolescents, being characterized by expression of genes and morphological and ultrastructural features of sarcomeric differentiation. The spindle cell variant of rhabdomyosarcoma (spindle cell RMS) in adults has been defined as an entity, separated from embryonal rhabdomyosarcoma (ERMS), with unfavourable clinical outcome. So far, no recurrent genetic alteration has been identified in the adult form of spindle cell RMS. We studied a case of adult spindle cell RMS using next-generation sequencing (NGS) after exome capture. Using this approach, we identified 31 tumour-specific somatic alterations and selected four genes with predicted functional relevance to muscle differentiation and growth. MYOD1, KIF18A, NOTCH1, and EML5 were further tested for mutations using Sanger sequencing on DNA from FFPE samples from 16 additional, adult spindle cell RMS samples. The highly conserved sequence homology of MYOD1 with other myogenic transcription factors prompted us to screen the basic DNA-binding domains of MYF5, MYF6 and MYOG for mutations. From the investigated 17 samples, seven (41%) showed homozygous mutation of MYOD1, indicating a critical role in this rare subtype of adult spindle cell RMS, while no mutations were found in any of the other genes involved in myogenic differentiation. The p.L122R mutation occurs in the conserved DNA binding domain in MYOD1 and leads to transactivation and MYC-like functions. MYOD1 homozygous mutations are frequent, recurrent and pathognomonic events in adult-type spindle cell RMS.

Yuan H, Qin F, Movassagh M, et al.
A chimeric RNA characteristic of rhabdomyosarcoma in normal myogenesis process.
Cancer Discov. 2013; 3(12):1394-403 [PubMed] Related Publications
UNLABELLED: Gene fusions and their chimeric products are common features of neoplasia. Given that many cancers arise by the dysregulated recapitulation of processes in normal development, we hypothesized that comparable chimeric gene products may exist in normal cells. Here, we show that a chimeric RNA, PAX3-FOXO1, identical to that found in alveolar rhabdomyosarcoma, is transiently present in cells undergoing differentiation from pluripotent cells into skeletal muscle. Unlike cells of rhabdomyosarcoma, these cells do not seem to harbor the t(2;13) chromosomal translocation. Importantly, both PAX3-FOXO1 RNA and protein could be detected in the samples of normal fetal muscle. Overexpression of the chimera led to continuous expression of MYOD and MYOG-two myogenic markers that are overexpressed in rhabdomyosarcoma cells. Our results are consistent with a developmental role of a specific chimeric RNA generated in normal cells without the corresponding chromosomal rearrangement at the DNA level seen in neoplastic cells presumably of the same lineage.
SIGNIFICANCE: A chimeric fusion RNA, PAX3-FOXO1, associated with alveolar rhabdomyosarcoma, is also present in normal non-cancer cells and tissues. Its transient expression nature and the absence of t(2;13) chromosomal translocation are consistent with a posttranscriptional mechanism. When constantly expressed, PAX3-FOXO1 interfered with the muscle differentiation process, which presumably contributes to tumorigenesis.

Annavarapu SR, Cialfi S, Dominici C, et al.
Characterization of Wnt/β-catenin signaling in rhabdomyosarcoma.
Lab Invest. 2013; 93(10):1090-9 [PubMed] Related Publications
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children and accounts for about 5% of all malignant paediatric tumours. β-Catenin, a multifunctional nuclear transcription factor in the canonical Wnt signaling pathway, is active in myogenesis and embryonal somite patterning. Dysregulation of Wnt signaling facilitates tumour invasion and metastasis. This study characterizes Wnt/β-catenin signaling and functional activity in paediatric embryonal and alveolar RMS. Immunohistochemical assessment of paraffin-embedded tissues from 44 RMS showed β-catenin expression in 26 cases with cytoplasmic/membranous expression in 9/14 cases of alveolar RMS, and 15/30 cases of embryonal RMS, whereas nuclear expression was only seen in 2 cases of embryonal RMS. The potential functional significance of β-catenin expression was tested in four RMS cell lines, two derived from embryonal (RD and RD18) RMS and two from alveolar (Rh4 and Rh30) RMS. Western blot analysis demonstrated the expression of Wnt-associated proteins including β-catenin, glycogen synthase kinase-3β, disheveled, axin-1, naked, LRP-6 and cadherins in all cell lines. Cell fractionation and immunofluorescence studies of the cell lines (after stimulation by human recombinant Wnt3a) showed reduced phosphorylation of β-catenin, stabilization of the active cytosolic form and nuclear translocation of β-catenin. Reporter gene assay demonstrated a T-cell factor/lymphoid-enhancing factor-mediated transactivation in these cells. In response to human recombinant Wnt3a, the alveolar RMS cells showed a significant decrease in proliferation rate and induction of myogenic differentiation (myogenin, MyoD1 and myf5). These data indicate that the central regulatory components of canonical Wnt/β-catenin signaling are expressed and that this pathway is functionally active in a significant subset of RMS tumours and might represent a novel therapeutic target.

Choi EY, Thomas DG, McHugh JB, et al.
Undifferentiated small round cell sarcoma with t(4;19)(q35;q13.1) CIC-DUX4 fusion: a novel highly aggressive soft tissue tumor with distinctive histopathology.
Am J Surg Pathol. 2013; 37(9):1379-86 [PubMed] Related Publications
A subset of small round cell sarcomas remains difficult to classify. Among these, a rare tumor harboring a t(4;19)(q35;q13.1) with CIC-DUX4 fusion has been described. The aim of this study is to better understand its clinicopathologic features. Four cases of CIC-DUX4 sarcoma, all arising in adults (3 women, 1 man, aged 20 to 43 y), were identified using conventional cytogenetic, reverse transcription polymerase chain reaction (RT-PCR) and fluorescence in situ hybridization (FISH) methods. All 4 tumors demonstrated CIC-DUX4 fusion transcript by both RT-PCR and FISH and CIC rearrangement by FISH. Cytogenetic results from 2 tumors showed t(4;19)(q35;q13.1) occurring as part of a simple karyotype in 1 tumor and as part of a complex karyotype in the other, the latter from a postchemotherapy specimen. Both tumors harbored trisomy 8 and lacked any other known sarcoma-associated translocation. No EWS or SYT rearrangements were detected by RT-PCR or FISH. The tumors had small round cell morphology with a distinctive constellation of histologic features including extensive geographic necrosis, mild nuclear pleomorphism with coarse chromatin and prominent nucleoli, clear cell areas, and focal myxoid matrix. Only focal staining for CD99 was present in each tumor. Two had very focal cytokeratin staining. All tumors were negative for desmin, myogenin, TLE-1, and S100 protein, whereas nuclear INI-1 staining was retained. The tumors were highly aggressive, and all patients died of disseminated disease within 16.8 months. CIC-DUX4 sarcoma represents a novel translocation-associated sarcoma with distinctive histopathologic features and rapid disease progression.

Kubota F, Matsuyama A, Shibuya R, et al.
Desmin-positivity in spindle cells: under-recognized immunophenotype of lipoblastoma.
Pathol Int. 2013; 63(7):353-7 [PubMed] Related Publications
Lipoblastoma is a distinct benign fatty tumor composed of adipocytes, lipoblasts, and primitive mesenchymal cells with a myxoid stroma. Lipoblastoma harbors characteristic fusion genes involving the PLAG1, resulting in aberrant expression of PLAG1. However, the nature of the primitive mesenchymal cells remains obscure. In our routine pathology practice, we noticed desmin-positive spindle mesenchymal cells in lipoblastomas, which is a hitherto poorly described phenomenon. Thus, we examined the expression of several myogenic markers including desmin in a variety of 95 mesenchymal tumors with fatty elements. Fourteen of the 15 lipoblastomas examined contained desmin-positive spindle cells, which also showed nuclear expression of PLAG1, whereas α-smooth muscle actin, muscle specific actin, h-caldesmon, and myogenin were negative. Some spindle cells in subsets of atypical lipomatous tumors/well differentiated liposarcomas (6/20), dedifferentiated liposarcomas (11/31) and pleomorphic liposarcomas (2/10) were positive for actins and/or desmin, supporting focal myofibroblastic or smooth muscle differentiation. The other tumors, including 11 myxoid/round cell liposarcomas, four spindle cell lipomas, and four lipofibromatoses, were negative for all of the myogenic markers assessed. The almost consistent desmin expression in spindle mesenchymal cells suggests a potential diagnostic utility of this marker and myofibroblastic phenotype of fractions in lipoblastoma cells.

Hettmer S, Teot LA, van Hummelen P, et al.
Mutations in Hedgehog pathway genes in fetal rhabdomyomas.
J Pathol. 2013; 231(1):44-52 [PubMed] Article available free on PMC after 15/08/2015 Related Publications
Ligand-independent, constitutive activation of Hedgehog signalling in mice expressing a mutant, activated SmoM2 allele results in the development of multifocal, highly differentiated tumours that express myogenic markers (including desmin, actin, MyoD and myogenin). The histopathology of these tumours, commonly classified as rhabdomyosarcomas, more closely resembles human fetal rhabdomyoma (FRM), a benign tumour that can be difficult to distinguish from highly differentiated rhabdomyosarcomas. We evaluated the spectrum of Hedgehog (HH) pathway gene mutations in a cohort of human FRM tumours by targeted Illumina sequencing and fluorescence in situ hybridization testing for PTCH1. Our studies identified functionally relevant aberrations at the PTCH1 locus in three of five FRM tumours surveyed, including a PTCH1 frameshift mutation in one tumour and homozygous deletions of PTCH1 in two tumours. These data suggest that activated Hedgehog signalling contributes to the biology of human FRM.

Sharma V, Harafuji N, Belayew A, Chen YW
DUX4 differentially regulates transcriptomes of human rhabdomyosarcoma and mouse C2C12 cells.
PLoS One. 2013; 8(5):e64691 [PubMed] Article available free on PMC after 15/08/2015 Related Publications
Facioscapulohumeral muscular dystrophy (FSHD) is linked to the deletion of the D4Z4 arrays at chromosome 4q35. Recent studies suggested that aberrant expression of double homeobox 4 (DUX4) from the last D4Z4 repeat causes FSHD. The aim of this study is to determine transcriptomic responses to ectopically expressed DUX4 in human and mouse cells of muscle lineage. We expression profiled human rhabdomyosarcoma (RD) cells and mouse C2C12 cells transfected with expression vectors of DUX4 using the Affymetrix Human Genome U133 Plus 2.0 Arrays and Mouse Genome 430 2.0 Arrays, respectively. A total of 2267 and 150 transcripts were identified to be differentially expressed in the RD and C2C12 cells, respectively. Amongst the transcripts differentially expressed in the RD cells, MYOD and MYOG (2 fold, p<0.05), and six MYOD downstream targets were up-regulated in RD but not C2C12 cells. Furthermore, 13 transcripts involved in germline function were dramatically induced only in the RD cells expressing DUX4. The top 3 IPA canonical pathways affected by DUX4 were different between the RD (inflammation, BMP signaling and NRF-2 mediated oxidative stress) and the C2C12 cells (p53 signaling, cell cycle regulation and cellular energy metabolism). Amongst the 40 transcripts shared by the RD and C2C12 cells, UTS2 was significantly induced by 76 fold and 224 fold in the RD and C2C12 cells, respectively. The differential expression of MYOD, MYOG and UTS2 were validated using real-time quantitative RT-PCR. We further validated the differentially expressed genes in immortalized FSHD myoblasts and showed up-regulation of MYOD, MYOG, ZSCAN4 and UTS2. The results suggest that DUX4 regulates overlapped and distinct groups of genes and pathways in human and mouse cells as evident by the selective up-regulation of genes involved in myogenesis and gametogenesis in human RD and immortalized cells as well as the different molecular pathways identified in the cells.

Koczkowska M, Lipska BS, Grzeszewska J, et al.
Primary leiomyosarcoma of the mesentery in two sisters: clinical and molecular characteristics.
Pol J Pathol. 2013; 64(1):59-63 [PubMed] Related Publications
Mesenteric leiomyosarcoma (LMS) is a very rare malignancy whose familiar occurrence has not yet been reported. We present two sisters who developed intestinal LMS. Pathological analysis of the tumor samples, including evaluation of smooth muscle actin+, desmin+, Myf4-, DOG-1-, S100-, CD34- and CD117- confirmed LMS diagnosis. Molecular analysis of the lesions, both primary tumors and a liver metastasis, revealed several genomic imbalances, with recurrent chromosomal aberration: interstitial gain at chromosome 17p11.2-13.1 with the minimal overlapping region of 9.2 Mb. Our study provides further evidence for the significant role of the genes located in this region in the early stage of carcinogenesis.

Zheng S, Huang KE, Jia J, et al.
Rhabdomyosarcomatous differentiation in gastrointestinal stromal tumors after imatinib resistance: a potential diagnostic pitfall.
Exp Biol Med (Maywood). 2013; 238(1):120-4 [PubMed] Related Publications
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumor of the digestive tract and characterized by expression of protein-tyrosine kinase (KIT) protein. Treatment of advanced GISTs has been improved dramatically following the development of imatinib. Despite the often long-lasting clinical benefit seen in most patients treated with imatinib, many will eventually suffer disease progression. In general, progressing GISTs retain their typical morphology. In this study, we present a patient with metastatic GISTs, who received more than 16 months of treatment with imatinib and whose tumors changed their morphological and immunohistochemical characteristics after imatinib-resistance. Histological, immunohistochemical and mutational analysis was performed on the prior and post-imatinib treatment GIST samples. The imatinib-resistant tumor cells in the progressing metastases showed marked pleomorphism which proved to be rhabdomyoblastic differentiation with Desmin and Myogenin immunopositivity. However, there was no secondary mutation of KIT, PDGFRA, KRAS and BRAF genes found in the imatinib-resistant lesion, except primary KIT V559D mutation. To our knowledge, this case represents the few reports on this unusual type of transdifferentiation in GISTs under imatinib therapy. Awareness of this phenomenon would help to avoid diagnostic confusion when evaluating post-imatinib samples from GISTs.

Walters ZS, Villarejo-Balcells B, Olmos D, et al.
JARID2 is a direct target of the PAX3-FOXO1 fusion protein and inhibits myogenic differentiation of rhabdomyosarcoma cells.
Oncogene. 2014; 33(9):1148-57 [PubMed] Article available free on PMC after 15/08/2015 Related Publications
Rhabdomyosarcomas (RMS) are the most frequent soft-tissue sarcoma in children and characteristically show features of developing skeletal muscle. The alveolar subtype is frequently associated with a PAX3-FOXO1 fusion protein that is known to contribute to the undifferentiated myogenic phenotype of RMS cells. Histone methylation of lysine residues controls developmental processes in both normal and malignant cell contexts. Here we show that JARID2, which encodes a protein known to recruit various complexes with histone-methylating activity to their target genes, is significantly overexpressed in RMS with PAX3-FOXO1 compared with the fusion gene-negative RMS (t-test; P < 0.0001). Multivariate analyses showed that higher JARID2 levels are also associated with metastases at diagnosis, independent of fusion gene status and RMS subtype (n = 120; P = 0.039). JARID2 levels were altered by silencing or overexpressing PAX3-FOXO1 in RMS cell lines with and without the fusion gene, respectively. Consistent with this, we demonstrated that JARID2 is a direct transcriptional target of the PAX3-FOXO1 fusion protein. Silencing JARID2 resulted in reduced cell proliferation coupled with myogenic differentiation, including increased expression of Myogenin (MYOG) and Myosin Light Chain (MYL1) in RMS cell lines representative of both the alveolar and embryonal subtypes. Induced myogenic differentiation was associated with a decrease in JARID2 levels and this phenotype could be rescued by overexpressing JARID2. Furthermore, we that showed JARID2 binds to and alters the methylation status of histone H3 lysine 27 in the promoter regions of MYOG and MYL1 and that the interaction of JARID2 at these promoters is dependent on EED, a core component of the polycomb repressive complex 2 (PRC2). Therefore, JARID2 is a downstream effector of PAX3-FOXO1 that maintains an undifferentiated myogenic phenotype that is characteristic of RMS. JARID2 and other components of PRC2 may represent novel therapeutic targets for treating RMS patients.

Yoshida A, Shibata T, Wakai S, et al.
Anaplastic lymphoma kinase status in rhabdomyosarcomas.
Mod Pathol. 2013; 26(6):772-81 [PubMed] Related Publications
Rhabdomyosarcoma is a rare soft tissue sarcoma that typically affects children, adolescents, and young adults. Despite treatment via a multidisciplinary approach, the prognosis of advance-stage rhabdomyosarcomas remains poor, and a new treatment strategy is needed. Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase that is a potential target for specific inhibitors. In this study, we investigated 116 rhabdomyosarcomas using a polymer-based ALK immunostaining method and correlated the results with clinicopathological parameters. In addition, we examined ALK status using dual-color fluorescence in situ hybridization, PCR, and sequencing. In immunohistochemical analysis, ALK was detected in 2 (6%) of 33 embryonal rhabdomyosarcomas, 42 (69%) of 61 alveolar rhabdomyosarcomas, and 0 (0%) of 22 other subtypes, including pleomorphic, adult-spindle-cell/sclerosing, and epithelioid variants. Compared with ALK-negative alveolar rhabdomyosarcomas, ALK-positive ones are presented with metastatic spread more frequently and showed a greater extent of myogenin reactivity. Overall survival was not associated with ALK expression. FOXO1 rearrangement was significantly associated with ALK immunoreactivity. The median ALK copy number was greater in ALK-positive tumors than in ALK-negative tumors. Most (93%) cases tested showed no selective increase in the ALK gene dosage. ALK selective amplification and low-level selective gain were noted in one and three cases, respectively. Further, a high-polysomy pattern (≥4 ALK copies in ≥40% of cells) was observed in seven cases. A significant increase in the ALK copy number was exclusive to the ALK-immunopositive cohort, but it was uncommon, accounting for only 30% of the 37 ALK-positive rhabdomyosarcomas. ALK gene rearrangement was not observed in either cohort, while an ALK somatic mutation (I1277T) was found in one ALK-negative embryonal case. Although it remains controversial whether ALK expression without gene rearrangement is therapeutically relevant, this comprehensive analysis may help future studies on the utility of ALK-targeted therapy for patients with rhabdomyosarcoma.

Plourde KV, Labrie Y, Desjardins S, et al.
Analysis of ZNF350/ZBRK1 promoter variants and breast cancer susceptibility in non-BRCA1/2 French Canadian breast cancer families.
J Hum Genet. 2013; 58(2):59-66 [PubMed] Related Publications
ZNF350/ZBRK1 is a transcription factor, which associates with BRCA1 to co-repress GADD45A to regulate DNA damage repair, and the expression of ZNF350 is altered in different human carcinomas. In a previous study, we identified ZNF350 genomic variants potentially involved in breast cancer susceptibility in high-risk non-BRCA1/2 breast cancer individuals, which pointed toward a potential association for variants in the 5'-UTR and promoter regions. Therefore, direct sequencing was undertaken and identified 12 promoter variants, whereas haplotype analyses put in evidence four common haplotypes with a frequency>2%. However, based on their frequency observed in breast cancer and unrelated healthy individuals, these are not statistically associated with breast cancer risk. Luciferase promoter assays in two breast cancer cell lines identified two haplotypes (H11 and H12) stimulating significantly the expression of ZNF350 transcript compared with the common haplotype H8. The high expression of the H11 allele was associated with the variant c.-874A. Using MatInspector and Transcription Element Search softwares, in silico analyses predicted that the variant c.-874A created a binding site for the factors c-Myc and myogenin. This study represents the first characterization step of the ZNF350 promoter. Additional studies in larger cohorts and other populations will be needed to further evaluate whether common and/or rare ZNF350 promoter variants and haplotypes could be associated with a modest risk of breast cancer.

Hasumi H, Baba M, Hasumi Y, et al.
Regulation of mitochondrial oxidative metabolism by tumor suppressor FLCN.
J Natl Cancer Inst. 2012; 104(22):1750-64 [PubMed] Article available free on PMC after 15/08/2015 Related Publications
BACKGROUND: Birt-Hogg-Dubé (BHD) syndrome is a hereditary hamartoma syndrome that predisposes patients to develop hair follicle tumors, lung cysts, and kidney cancer. Genetic studies of BHD patients have uncovered the causative gene, FLCN, but its function is incompletely understood.
METHODS: Mice with conditional alleles of FLCN and/or peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PPARGC1A), a transcriptional coactivator that regulates mitochondrial biogenesis, were crossbred with mice harboring either muscle creatine kinase (CKM) -Cre or myogenin (MYOG) -Cre transgenes to knock out FLCN and/or PPARGC1A in muscle, or cadherin 16 (CDH16)- Cre transgenes to knock out FLCN and/or PPARGC1A in kidney. Real-time polymerase chain reaction, immunoblotting, electron microscopy, and metabolic profiling assay were performed to evaluate mitochondrial biogenesis and function in muscle. Immunoblotting, electron microscopy, and histological analysis were used to investigate expression and the pathological role of PPARGC1A in FLCN-deficient kidney. Real-time polymerase chain reaction, oxygen consumption measurement, and flow cytometry were carried out using a FLCN-null kidney cancer cell line. All statistical analyses were two-sided.
RESULTS: Muscle-targeted FLCN knockout mice underwent a pronounced metabolic shift toward oxidative phosphorylation, including increased mitochondrial biogenesis (FLCN ( f/f ) vs FLCN ( f/f ) /CKM-Cre: % mitochondrial area mean = 7.8% vs 17.8%; difference = 10.0%; 95% confidence interval = 5.7% to 14.3%; P < .001), and the observed increase in mitochondrial biogenesis was PPARGC1A dependent. Reconstitution of FLCN-null kidney cancer cells with wild-type FLCN suppressed mitochondrial metabolism and PPARGC1A expression. Kidney-targeted PPARGC1A inactivation partially rescued the enlarged kidney phenotype and abrogated the hyperplastic cells observed in the FLCN-deficient kidney.
CONCLUSION: FLCN deficiency and subsequent increased PPARGC1A expression result in increased mitochondrial function and oxidative metabolism as the source of cellular energy, which may give FLCN-null kidney cells a growth advantage and drive hyperplastic transformation.

Hettmer S, Liu J, Miller CM, et al.
Sarcomas induced in discrete subsets of prospectively isolated skeletal muscle cells.
Proc Natl Acad Sci U S A. 2011; 108(50):20002-7 [PubMed] Article available free on PMC after 15/08/2015 Related Publications
Soft-tissue sarcomas are heterogeneous cancers that can present with tissue-specific differentiation markers. To examine the cellular basis for this histopathological variation and to identify sarcoma-relevant molecular pathways, we generated a chimeric mouse model in which sarcoma-associated genetic lesions can be introduced into discrete, muscle-resident myogenic and mesenchymal cell lineages. Expression of Kirsten rat sarcoma viral oncogene [Kras(G12V)] and disruption of cyclin-dependent kinase inhibitor 2A (CDKN2A; p16p19) in prospectively isolated satellite cells gave rise to pleomorphic rhabdomyosarcomas (MyoD-, Myogenin- and Desmin-positive), whereas introduction of the same oncogenetic hits in nonmyogenic progenitors induced pleomorphic sarcomas lacking myogenic features. Transcriptional profiling demonstrated that myogenic and nonmyogenic Kras; p16p19(null) sarcomas recapitulate gene-expression signatures of human rhabdomyosarcomas and identified a cluster of genes that is concordantly up-regulated in both mouse and human sarcomas. This cluster includes genes associated with Ras and mechanistic target of rapamycin (mTOR) signaling, a finding consistent with activation of the Ras and mTOR pathways both in Kras; p16p19(null) sarcomas and in 26-50% of human rhabdomyosarcomas surveyed. Moreover, chemical inhibition of Ras or mTOR signaling arrested the growth of mouse Kras; p16p19(null) sarcomas and of human rhabdomyosarcoma cells in vitro and in vivo. Taken together, these data demonstrate the critical importance of lineage commitment within the tumor cell-of-origin in determining sarcoma histotype and introduce an experimental platform for rapid dissection of sarcoma-relevant cellular and molecular events.

Al-Tahan A, Sarkis O, Harajly M, et al.
Retinoic acid fails to induce cell cycle arrest with myogenic differentiation in rhabdomyosarcoma.
Pediatr Blood Cancer. 2012; 58(6):877-84 [PubMed] Related Publications
BACKGROUND: Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. Current treatment strategies do not cure most children with recurrent or high-risk disease, underlying the need for novel therapeutic approaches. Retinoic acid has been shown to induce differentiation in a variety of cells including skeletal myoblasts and neuroblasts. In the setting of minimal residual disease, retinoic acid improves survival in neuroblastoma, another poorly differentiated childhood tumor. Whether such an approach is useful for rhabdomyosarcoma has not yet been investigated. Several in vitro studies have demonstrated an appreciable effect of retinoic acid on human RMS cellular proliferation and differentiation.
PROCEDURE: We assessed the efficacy of ATRA on rhabdomyosarcoma, in vitro and in vivo, using cell lines and xenografts.
RESULTS: ATRA slowed RMS cell proliferation, and promoted a more differentiated myogenic phenotype in both alveolar and embryonal RMS cell lines. Treatment of cultured murine myoblasts with retinoids increased Myogenin expression, but did not induce cell cycle arrest. Despite the favorable in vitro effects, ATRA failed to delay relapse of minimal residual disease using human RMS xenografts in immuno-suppressed NOD-SCID (NSG) mice. Interestingly, tumors that recurred after ATRA treatment showed evidence of enhanced muscle differentiation.
CONCLUSION: Our results indicate that ATRA could increase the expression of some genes associated with muscle differentiation in rhabdomyosarcoma cells, but there was no benefit of single-agent therapy in an MRD model, likely because cell cycle arrest was uncoupled from the pro-differentiation effects of retinoids.

Krskova L, Augustinakova A, Drahokoupilova E, et al.
Rhabdomyosarcoma: molecular analysis of Igf2, MyoD1 and Myogenin expression.
Neoplasma. 2011; 58(5):415-23 [PubMed] Related Publications
Rhabdomyosarcoma is the most common soft tissue sarcoma of childhood. There are two major histopathological types of RMS – embryonal (eRMS) and alveolar (aRMS). A molecular study of Igf2, MyoD1 and Myogenin was performed to determine the expression profiles and to assess the possible utility of these genes as potential treatment targets. Patients with RMS showed up to 100-fold increase of Igf2 transcription in comparison with normal skeletal muscle. Our data suggest that overexpression of Igf2 occurs in RMS of both histological subtypes. No correlation between the results of Igf2 mRNA expression and LOH at the 11p15 region (p= 0.12) was observed, but there was a trend of a higher expression of Igf2 mRNA in RMS samples with LOH. We observed a high level of MyoD1 mRNA in both aRMS and eRMS, and we detected a similar level of MyoD1 mRNA in RMS and normal skeletal muscles. There was a correlation between the results of MyoD1 mRNA expression and LOH at the 11p15 region.We did not observe any statistical difference in the level of Myogenin mRNA in the subgroups of RMS. Analogous to MyoD1, we observed a similar level of Myogenin mRNA in RMS and normal skeletal muscles.

Hosoyama T, Aslam MI, Abraham J, et al.
IL-4R drives dedifferentiation, mitogenesis, and metastasis in rhabdomyosarcoma.
Clin Cancer Res. 2011; 17(9):2757-66 [PubMed] Article available free on PMC after 15/08/2015 Related Publications
PURPOSE: Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in childhood. The alveolar subtype of rhabdomyosarcoma (ARMS) is a paradigm for refractory and incurable solid tumors because more than half of the children at diagnosis have either regional lymph node or distant metastases. These studies follow our previous observation that Interleukin-4 receptor α (IL-4Rα) is upregulated in both human and murine ARMS, and that the IL-4R signaling pathway may be a target for abrogating tumor progression.
EXPERIMENTAL DESIGN: By in vitro biochemical and cell biology studies as well as preclinical studies using a genetically engineered mouse model, we evaluated the role of IL-4 and IL-13 in IL-4R-mediated mitogenesis, myodifferentiation, and tumor progression.
RESULTS: IL-4 and IL-13 ligands accelerated tumor cell growth and activated STAT6, Akt, or MAPK signaling pathways in the human RMS cell lines, RD and Rh30, as well as in mouse primary ARMS cell cultures. IL-4 and IL-13 treatment also decreased protein expression of myogenic differentiation factors MyoD and Myogenin, indicating a loss of muscle differentiation. Using a genetically engineered mouse model of ARMS, we have shown that inhibition of IL-4R signaling pathway with a neutralizing antibody has a profound effect on the frequency of lymph node and pulmonary metastases, resulting in significant survival extension in vivo.
CONCLUSIONS: Our results indicate that an IL-4R-dependent signaling pathway regulates tumor cell progression in RMS, and inhibition of this pathway could be a promising adjuvant therapeutic approach.

Lee MH, Jothi M, Gudkov AV, Mal AK
Histone methyltransferase KMT1A restrains entry of alveolar rhabdomyosarcoma cells into a myogenic differentiated state.
Cancer Res. 2011; 71(11):3921-31 [PubMed] Article available free on PMC after 15/08/2015 Related Publications
Alveolar rhabdomyosarcoma (ARMS) is an aggressive pediatric muscle cancer, which arrested during the process of skeletal muscle differentiation. In muscle myoblast cells, ectopic expression of the histone H3 lysine 9 (H3K9) methytransferase KMT1A blocks differentiation by repressing a myogenic gene expression program. In this study, we tested the hypothesis that activation of a KMT1A-mediated program of transcriptional repression prevents ARMS cells from differentiating. We investigated whether KMT1A represses the expression of differentiation-associated genes in ARMS cells, thereby blocking muscle differentiation. Our results show that expression of KMT1A is induced in human ARMS cancer cell lines when cultured under differentiation-permissible conditions. shRNA-mediated knockdown of KMT1A decreased anchorage dependent and independent cell proliferation and tumor xenograft growth, increased expression of differentiation-associated genes, and promoted the appearance of a terminally differentiated-like phenotype. Finally, shRNA-directed KMT1A knockdown restored the impaired transcriptional activity of the myogenic regulator MyoD. Together, our results suggested that high levels of KMT1A in ARMS cells under differentiation conditions impairs MyoD function, thereby arresting myogenic differentiation in these tumor cells. Thus, targeting KMT1A may be a novel strategy for the treatment of this disease.

Bhutoria S, Oneil C
Embryonal rhabdomyosarcoma of the adult soft palate.
Indian J Pathol Microbiol. 2011 Jan-Mar; 54(1):136-7 [PubMed] Related Publications
Embryonal rhabdomyosarcoma is the most common soft tissue sarcoma in children. We report a rare case of embryonal rhabdomyosarcoma of the soft palate in a 32-year-old Caucasian female. Detailed histology of the tumor is described. Positive staining with desmin, myogenin and myoD1 confirmed the tumor to be embryonal rhabdomyosarcoma. A genetic association between rhabdomyosarcoma, polycystic ovary syndrome and the FEM1A gene on the human chromosome is speculated upon.

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