Cell-Cycle Dependent Expression of a Translocation-Mediated Fusion Oncogene Mediates Checkpoint Adaptation in Rhabdomyosarcoma

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Rhabdomyosarcoma is the most commonly occurring soft-tissue sarcoma in childhood. Most rhabdomyosarcoma falls into one of two biologically distinct subgroups represented by alveolar or embryonal histology. The alveolar subtype harbors a translocation-mediated PAX3:FOXO1A fusion gene and has an extremely poor prognosis. However, tumor cells have heterogeneous expression for the fusion gene. Using a conditional genetic mouse model as well as human tumor cell lines, we show that that Pax3:Foxo1a expression is enriched in G₂ and triggers a transcriptional program conducive to checkpoint adaptation under stress conditions such as irradiation in vitro and in vivo. Pax3:Foxo1a also tolerizes tumor cells to clinically-established chemotherapy agents and emerging molecularly-targeted agents. Thus, the surprisingly dynamic regulation of the Pax3:Foxo1a locus is a paradigm that has important implications for the way in which oncogenes are modeled in cancer cells.

Vyšlo v časopise: Cell-Cycle Dependent Expression of a Translocation-Mediated Fusion Oncogene Mediates Checkpoint Adaptation in Rhabdomyosarcoma. PLoS Genet 10(1): e32767. doi:10.1371/journal.pgen.1004107
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004107

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1. BrenemanJC, LydenE, PappoAS, LinkMP, AndersonJR, et al. (2003) Prognostic factors and clinical outcomes in children and adolescents with metastatic rhabdomyosarcoma–a report from the Intergroup Rhabdomyosarcoma Study IV. J Clin Oncol 21: 78–84.

2. AndersonJR, BarrFG, HawkinsDS, ParhamDM, SkapekSX, et al. (2010) Fusion-negative alveolar rhabdomyosarcoma: modification of risk stratification is premature. J Clin Oncol 28: e587–588; author reply e589–590.

3. WilliamsonD, MissiagliaE, de ReyniesA, PierronG, ThuilleB, et al. (2010) Fusion gene-negative alveolar rhabdomyosarcoma is clinically and molecularly indistinguishable from embryonal rhabdomyosarcoma. J Clin Oncol 28: 2151–2158.

4. WexlerLH, LadanyiM (2010) Diagnosing alveolar rhabdomyosarcoma: morphology must be coupled with fusion confirmation. J Clin Oncol 28: 2126–2128.

5. KellerC, ArenkielBR, CoffinCM, El-BardeesyN, DePinhoRA, et al. (2004) Alveolar rhabdomyosarcomas in conditional Pax3:Fkhr mice: cooperativity of Ink4a/ARF and Trp53 loss of function. Genes Dev 18: 2614–2626.

6. KellerC, HansenMS, CoffinCM, CapecchiMR (2004) Pax3:Fkhr interferes with embryonic Pax3 and Pax7 function: implications for alveolar rhabdomyosarcoma cell of origin. Genes Dev 18: 2608–2613.

7. NishijoK, ChenQR, ZhangL, McCleishAT, RodriguezA, et al. (2009) Credentialing a preclinical mouse model of alveolar rhabdomyosarcoma. Cancer Res 69: 2902–2911.

8. TaniguchiE, NishijoK, McCleishAT, MichalekJE, GraysonMH, et al. (2008) PDGFR-A is a therapeutic target in alveolar rhabdomyosarcoma. Oncogene 27: 6550–6560.

9. CaoL, YuY, BilkeS, WalkerRL, MayeenuddinLH, et al. (2010) Genome-Wide Identification of PAX3-FKHR Binding Sites in Rhabdomyosarcoma Reveals Candidate Target Genes Important for Development and Cancer. Cancer Res 70: 6497–508.

10. OsukaS, SampetreanO, ShimizuT, SagaI, OnishiN, et al. (2013) IGF1 receptor signaling regulates adaptive radioprotection in glioma stem cells. Stem cells 31: 627–640.

11. NurseP (1994) Ordering S phase and M phase in the cell cycle. Cell 79: 547–550.

12. BerryLD, GouldKL (1996) Regulation of Cdc2 activity by phosphorylation at T14/Y15. Progress in cell cycle research 2: 99–105.

13. SyljuasenRG, JensenS, BartekJ, LukasJ (2006) Adaptation to the ionizing radiation-induced G2 checkpoint occurs in human cells and depends on checkpoint kinase 1 and Polo-like kinase 1 kinases. Cancer Res 66: 10253–10257.

14. SyljuasenRG (2007) Checkpoint adaptation in human cells. Oncogene 26: 5833–5839.

15. YooHY, KumagaiA, ShevchenkoA, ShevchenkoA, DunphyWG (2004) Adaptation of a DNA replication checkpoint response depends upon inactivation of Claspin by the Polo-like kinase. Cell 117: 575–588.

16. CaoL, YuY, BilkeS, WalkerRL, MayeenuddinLH, et al. (2010) Genome-wide identification of PAX3-FKHR binding sites in rhabdomyosarcoma reveals candidate target genes important for development and cancer. Cancer Res 70: 6497–6508.

17. AbrahamJ, ChuaYX, GloverJM, TynerJW, LoriauxMM, et al. (2012) An adaptive Src-PDGFRA-Raf axis in rhabdomyosarcoma. Biochem Biophys Res Commun 426: 363–368.

18. KitzmannM, CarnacG, VandrommeM, PrimigM, LambNJ, et al. (1998) The muscle regulatory factors MyoD and myf-5 undergo distinct cell cycle-specific expression in muscle cells. J Cell Biol 142: 1447–1459.

19. Batonnet-PichonS, TintignacLJ, CastroA, SirriV, LeibovitchMP, et al. (2006) MyoD undergoes a distinct G2/M-specific regulation in muscle cells. Exp Cell Res 312: 3999–4010.

20. KoniarasK, CuddihyAR, ChristopoulosH, HoggA, O'ConnellMJ (2001) Inhibition of Chk1-dependent G2 DNA damage checkpoint radiosensitizes p53 mutant human cells. Oncogene 20: 7453–7463.

21. ClemensonC, Marsolier-KergoatMC (2009) DNA damage checkpoint inactivation: adaptation and recovery. DNA Repair (Amst) 8: 1101–1109.

22. HanksS, ColemanK, ReidS, PlajaA, FirthH, et al. (2004) Constitutional aneuploidy and cancer predisposition caused by biallelic mutations in BUB1B. Nat Genet 36: 1159–1161.

23. Kowal-VernA, Gonzalez-CrussiF, TurnerJ, TrujilloYP, ChouP, et al. (1990) Flow and image cytometric DNA analysis in rhabdomyosarcoma. Cancer Res 50: 6023–6027.

24. San Miguel-FraileP, Carrillo-GijonR, Rodriguez-PeraltoJL, BadiolaIA (2004) Prognostic significance of DNA ploidy and proliferative index (MIB-1 index) in childhood rhabdomyosarcoma. Am J Clin Pathol 121: 358–365.

25. ShapiroDN, ParhamDM, DouglassEC, AshmunR, WebberBL, et al. (1991) Relationship of tumor-cell ploidy to histologic subtype and treatment outcome in children and adolescents with unresectable rhabdomyosarcoma. J Clin Oncol 9: 159–166.

26. LiG, KikuchiK, RadkaM, AbrahamJ, RubinBP, et al. (2013) IL-4 receptor blockade abrogates satellite cell - rhabdomyosarcoma fusion and prevents tumor establishment. Stem cells 31: 2304–12.

27. WeihuaZ, LinQ, RamothAJ, FanD, FidlerIJ (2011) Formation of solid tumors by a single multinucleated cancer cell. Cancer 117: 4092–4099.

28. KikuchiK, SoundararajanA, ZarzabalLA, WeemsCR, NelonLD, et al. (2012) Protein kinase C iota as a therapeutic target in alveolar rhabdomyosarcoma. Oncogene 32: 286–95.

29. YamadaHY, RaoCV (2010) Genes that modulate the sensitivity for anti-microtubule drug-mediated chemotherapy. Curr Cancer Drug Targets 10: 623–633.

30. HuK, LeeC, QiuD, FotovatiA, DaviesA, et al. (2009) Small interfering RNA library screen of human kinases and phosphatases identifies polo-like kinase 1 as a promising new target for the treatment of pediatric rhabdomyosarcomas. Mol Cancer Ther 8: 3024–3035.

31. SkapekSX, AndersonJ, BarrFG, BridgeJA, Gastier-FosterJM, et al. (2013) PAX-FOXO1 Fusion Status Drives Unfavorable Outcome for Children With Rhabdomyosarcoma: A Children's Oncology Group Report. Pediatr Blood Cancer 60: 1411–7.

32. MissiagliaE, WilliamsonD, ChisholmJ, WirapatiP, PierronG, et al. (2012) PAX3/FOXO1 fusion gene status is the key prognostic molecular marker in rhabdomyosarcoma and significantly improves current risk stratification. J Clin Oncol 30: 1670–1677.

33. GuptaAA, AndersonJR, PappoAS, SpuntSL, DasguptaR, et al. (2012) Patterns of chemotherapy-induced toxicities in younger children and adolescents with rhabdomyosarcoma: a report from the Children's Oncology Group Soft Tissue Sarcoma Committee. Cancer 118: 1130–1137.

34. HaldarM, HancockJD, CoffinCM, LessnickSL, CapecchiMR (2007) A conditional mouse model of synovial sarcoma: insights into a myogenic origin. Cancer Cell 11: 375–388.

35. ZhuH, AcquavivaJ, RamachandranP, BoskovitzA, WoolfendenS, et al. (2009) Oncogenic EGFR signaling cooperates with loss of tumor suppressor gene functions in gliomagenesis. Proc Natl Acad Sci U S A 106: 2712–2716.

36. BerntKM, ZhuN, SinhaAU, VempatiS, FaberJ, et al. (2011) MLL-rearranged leukemia is dependent on aberrant H3K79 methylation by DOT1L. Cancer Cell 20: 66–78.

37. DiMartinoJF, MillerT, AytonPM, LandeweT, HessJL, et al. (2000) A carboxy-terminal domain of ELL is required and sufficient for immortalization of myeloid progenitors by MLL-ELL. Blood 96: 3887–3893.

38. TynerJW, WaltersDK, WillisSG, LuttroppM, OostJ, et al. (2008) RNAi screening of the tyrosine kinome identifies therapeutic targets in acute myeloid leukemia. Blood 111: 2238–2245.