Modulating the Strength and Threshold of NOTCH Oncogenic Signals by

English version České info

Oncogenes, which are essential for tumor initiation, development, and maintenance, are valuable targets for cancer therapy. However, it remains a challenge to effectively inhibit oncogene activity by targeting their downstream pathways without causing significant toxicity to normal tissues. Here we show that deletion of mir-181a-1/b-1 expression inhibits the development of Notch1 oncogene-induced T cell acute lymphoblastic leukemia (T-ALL). mir-181a-1/b-1 controls the strength and threshold of Notch activity in tumorigenesis in part by dampening multiple negative feedback regulators downstream of NOTCH and pre-T cell receptor (TCR) signaling pathways. Importantly, although Notch oncogenes utilize normal thymic progenitor cell genetic programs for tumor transformation, comparative analyses of mir-181a-1/b-1 function in normal thymocyte and tumor development demonstrate that mir-181a-1/b-1 can be specifically targeted to inhibit tumor development with little toxicity to normal development. Finally, we demonstrate that mir-181a-1/b-1, but not mir-181a-2b-2 and mir-181-c/d, controls the development of normal thymic T cells and leukemia cells. Together, these results illustrate that NOTCH oncogene activity in tumor development can be selectively inhibited by targeting the molecular networks controlled by mir-181a-1/b-1.

Vyšlo v časopise: Modulating the Strength and Threshold of NOTCH Oncogenic Signals by. PLoS Genet 8(8): e32767. doi:10.1371/journal.pgen.1002855
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1002855

Souhrn

Zdroje

1. HeL, ThomsonJM, HemannMT, Hernando-MongeE, MuD, et al. (2005) A microRNA polycistron as a potential human oncogene. Nature 435: 828–833.

2. MavrakisKJ, Van Der MeulenJ, WolfeAL, LiuX, MetsE, et al. (2011) A cooperative microRNA-tumor suppressor gene network in acute T-cell lymphoblastic leukemia (T-ALL). Nat Genet

3. CostineanS, ZanesiN, PekarskyY, TiliE, VoliniaS, et al. (2006) Pre-B cell proliferation and lymphoblastic leukemia/high-grade lymphoma in E(mu)-miR155 transgenic mice. Proc Natl Acad Sci U S A 103: 7024–7029.

4. MedinaPP, NoldeM, SlackFJ (2010) OncomiR addiction in an in vivo model of microRNA-21-induced pre-B-cell lymphoma. Nature 467: 86–90.

5. KotaJ, ChivukulaRR, O'DonnellKA, WentzelEA, MontgomeryCL, et al. (2009) Therapeutic microRNA delivery suppresses tumorigenesis in a murine liver cancer model. Cell 137: 1005–1017.

6. LiX, SandaT, LookAT, NovinaCD, von BoehmerH (2011) Repression of tumor suppressor miR-451 is essential for NOTCH1-induced oncogenesis in T-ALL. J Exp Med 208: 663–675.

7. HatleyME, PatrickDM, GarciaMR, RichardsonJA, Bassel-DubyR, et al. (2010) Modulation of K-Ras-dependent lung tumorigenesis by MicroRNA-21. Cancer Cell 18: 282–293.

8. BergerAH, KnudsonAG, PandolfiPP (2011) A continuum model for tumour suppression. Nature 476: 163–169.

9. SalmenaL, PolisenoL, TayY, KatsL, PandolfiPP (2011) A ceRNA hypothesis: the Rosetta Stone of a hidden RNA language? Cell 146: 353–358.

10. PearWS, AsterJC, ScottML, HasserjianRP, SofferB, et al. (1996) Exclusive development of T cell neoplasms in mice transplanted with bone marrow expressing activated Notch alleles. J Exp Med 183: 2283–2291.

11. WengAP, FerrandoAA, LeeW, MorrisJPt, SilvermanLB, et al. (2004) Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science 306: 269–271.

12. SmithMA (2009) Update on developmental therapeutics for acute lymphoblastic leukemia. Curr Hematol Malig Rep 4: 175–182.

13. PuiJC, AllmanD, XuL, DeRoccoS, KarnellFG, et al. (1999) Notch1 expression in early lymphopoiesis influences B versus T lineage determination. Immunity 11: 299–308.

14. LandgrafP, RusuM, SheridanR, SewerA, IovinoN, et al. (2007) A mammalian microRNA expression atlas based on small RNA library sequencing. Cell 129: 1401–1414.

15. ChenCZ, LiL, LodishHF, BartelDP (2004) MicroRNAs modulate hematopoietic lineage differentiation. Science 303: 83–86.

16. LiQJ, ChauJ, EbertPJ, SylvesterG, MinH, et al. (2007) miR-181a Is an Intrinsic Modulator of T Cell Sensitivity and Selection. Cell 129: 147–161.

17. KuchenS, ReschW, YamaneA, KuoN, LiZ, et al. (2010) Regulation of microRNA expression and abundance during lymphopoiesis. Immunity 32: 828–839.

18. SchotteD, ChauJC, SylvesterG, LiuG, ChenC, et al. (2009) Identification of new microRNA genes and aberrant microRNA profiles in childhood acute lymphoblastic leukemia. Leukemia 23: 313–322.

19. AllmanD, SambandamA, KimS, MillerJP, PaganA, et al. (2003) Thymopoiesis independent of common lymphoid progenitors. Nat Immunol 4: 168–174.

20. SchmittTM, de PooterRF, GronskiMA, ChoSK, OhashiPS, et al. (2004) Induction of T cell development and establishment of T cell competence from embryonic stem cells differentiated in vitro. Nat Immunol 5: 410–417.

21. LiuG, MinH, YueS, ChenCZ (2008) Pre-miRNA loop nucleotides control the distinct activities of mir-181a-1 and mir-181c in early T cell development. PLoS ONE 3: e3592 doi:10.1371/journal.pone.0003592.

22. CampeseAF, GarbeAI, ZhangF, GrassiF, ScrepantiI, et al. (2006) Notch1-dependent lymphomagenesis is assisted by but does not essentially require pre-TCR signaling. Blood 108: 305–310.

23. MaillardI, TuL, SambandamA, Yashiro-OhtaniY, MillhollandJ, et al. (2006) The requirement for Notch signaling at the beta-selection checkpoint in vivo is absolute and independent of the pre-T cell receptor. J Exp Med 203: 2239–2245.

24. AllmanD, KarnellFG, PuntJA, BakkourS, XuL, et al. (2001) Separation of Notch1 promoted lineage commitment and expansion/transformation in developing T cells. J Exp Med 194: 99–106.

25. ChiangMY, XuL, ShestovaO, HistenG, L'HeureuxS, et al. (2008) Leukemia-associated NOTCH1 alleles are weak tumor initiators but accelerate K-ras-initiated leukemia. J Clin Invest 118: 3181–3194.

26. YunTJ, BevanMJ (2003) Notch-regulated ankyrin-repeat protein inhibits Notch1 signaling: multiple Notch1 signaling pathways involved in T cell development. J Immunol 170: 5834–5841.

27. CiofaniM, SchmittTM, CiofaniA, MichieAM, CuburuN, et al. (2004) Obligatory role for cooperative signaling by pre-TCR and Notch during thymocyte differentiation. J Immunol 172: 5230–5239.

28. van EsJH, van GijnME, RiccioO, van den BornM, VooijsM, et al. (2005) Notch/gamma-secretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells. Nature 435: 959–963.

29. MedyoufH, AlcaldeH, BerthierC, GuilleminMC, dos SantosNR, et al. (2007) Targeting calcineurin activation as a therapeutic strategy for T-cell acute lymphoblastic leukemia. Nat Med 13: 736–741.

30. WengAP, NamY, WolfeMS, PearWS, GriffinJD, et al. (2003) Growth suppression of pre-T acute lymphoblastic leukemia cells by inhibition of notch signaling. Mol Cell Biol 23: 655–664.

31. HochstenbachF, BrennerMB (1989) T-cell receptor delta-chain can substitute for alpha to form a beta delta heterodimer. Nature 340: 562–565.

32. CichockiF, FelicesM, McCullarV, PresnellSR, Al-AttarA, et al. Cutting edge: microRNA-181 promotes human NK cell development by regulating Notch signaling. J Immunol 187: 6171–6175.

33. LewisBP, BurgeCB, BartelDP (2005) Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell 120: 15–20.

34. KerteszM, IovinoN, UnnerstallU, GaulU, SegalE (2007) The role of site accessibility in microRNA target recognition. Nat Genet 39: 1278–1284.

35. van DongenS, Abreu-GoodgerC, EnrightAJ (2008) Detecting microRNA binding and siRNA off-target effects from expression data. Nat Methods 5: 1023–1025.