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TRIB2 regulates the differentiation of MLL–TET1 transduced myeloid progenitor cells

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Abstract

The function and mechanism of action of MLL–TET1 (MT1) fusion protein in hematological cells are unclear and require further investigation. In the present study, we found that the MT1 fusion protein attenuated the expression of Cebpa, Csf1r, and Cd11b and inhibited the differentiation of myeloid progenitor cells. Increased binding of the MT1 fusion protein to the Trib2 promoter upregulated Trib2 mRNA and protein expression and downregulated Cebpa expression. Trib2 knockdown relieved the inhibition of myeloid cell differentiation induced by the MT1 fusion protein. Thus, TRIB2 is important for the survival of leukemia cells during MT1-related leukemogenesis and is important in maintaining differentiation blockade of leukemic cells.

Key messages

• MLL–TET1 fusion decreases the 5-hmC levels in the myeloid progenitor cells.

• MLL–TET1 fusion inhibits myeloid differentiation through decreased expression of Cebpa.

• MLL–TET1 fusion blocks the differentiation of the myeloid progenitor cells by overexpressing Trib2.

• Knockdown of Trib2 in MLL–TET1 transduced cells induces myeloid differentiation.

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References

  1. Cosgrove MS, Patel A (2010) Mixed lineage leukemia: a structure–function perspective of the MLL1 protein. FEBS J 277:1832–1842

    Article  CAS  Google Scholar 

  2. Bell JT, Pai AA, Pickrell JK, Gaffney DJ, Pique-Regi R, Degner JF, Gilad Y, Pritchard JK (2011) DNA methylation patterns associate with genetic and gene expression variation in HapMap cell lines. Genome Biol 12:R10

    Article  CAS  Google Scholar 

  3. Law JA, Jacobsen SE (2010) Establishing, maintaining and modifying DNA methylation patterns in plants and animals. Nat Rev Genet 11:204–220

    Article  CAS  Google Scholar 

  4. Tahiliani M, Koh KP, Shen Y, Pastor WA, Bandukwala H, Brudno Y, Agarwal S, Iyer LM, Liu DR, Aravind L, Rao A (2009) Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science 324:930–935

    Article  CAS  Google Scholar 

  5. Williams K, Christensen J, Pedersen MT, Johansen JV, Cloos PA, Rappsilber J, Helin K (2011) TET1 and hydroxymethylcytosine in transcription and DNA methylation fidelity. Nature 473:343–348

    Article  CAS  Google Scholar 

  6. Ito S, D'Alessio AC, Taranova OV, Hong K, Sowers LC, Zhang Y (2010) Role of Tet proteins in 5mC to 5hmC conversion, ES-cell self-renewal and inner cell mass specification. Nature 466:1129–1133

    Article  CAS  Google Scholar 

  7. Ko M, Huang Y, Jankowska AM, Pape UJ, Tahiliani M, Bandukwala HS, An J, Lamperti ED, Koh KP, Ganetzky R, Liu XS, Aravind L, Agarwal S, Maciejewski JP, Rao A (2010) Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2. Nature 468:839–843

    Article  CAS  Google Scholar 

  8. Mohr F, Dohner K, Buske C, Rawat VP (2011) TET genes: new players in DNA demethylation and important determinants for stemness. Exp Hematol 39:272–281

    Article  CAS  Google Scholar 

  9. Frauer C, Rottach A, Meilinger D, Bultmann S, Fellinger K, Hasenoder S, Wang M, Qin W, Soding J, Spada F et al (2011) Different binding properties and function of CXXC zinc finger domains in Dnmt1 and Tet1. PLoS One 6:e16627

    Article  CAS  Google Scholar 

  10. Lorsbach RB, Moore J, Mathew S, Raimondi SC, Mukatira ST, Downing JR (2003) TET1, a member of a novel protein family, is fused to MLL in acute myeloid leukemia containing the t(10;11)(q22;q23). Leukemia 17:637–641

    Article  CAS  Google Scholar 

  11. Lee SG, Cho SY, Kim MJ, Oh SH, Cho EH, Lee S, Baek EJ, Choi JH, Bohlander SK, Lode L, Richebourg S, Yoon HJ, Marschalek R, Meyer C, Park TS (2013) Genomic breakpoints and clinical features of MLL–TET1 rearrangement in acute leukemias. Haematologica 98:e55–e57

    Article  Google Scholar 

  12. Meyer C, Hofmann J, Burmeister T, Groger D, Park TS, Emerenciano M, Pombo de Oliveira M, Renneville A, Villarese P, Macintyre E et al (2013) The MLL recombinome of acute leukemias in 2013. Leukemia 27:2165–2176

    Article  CAS  Google Scholar 

  13. Ittel A, Jeandidier E, Helias C, Perrusson N, Humbrecht C, Lioure B, Mazurier I, Mayeur-Rousse C, Lavaux A, Thiebault S, Lerintiu F, Gervais C, Mauvieux L (2013) First description of the t(10;11)(q22;q23)/MLL–TET1 translocation in a T-cell lymphoblastic lymphoma, with subsequent lineage switch to acute myelomonocytic myeloid leukemia. Haematologica 98:e166–e168

    Article  Google Scholar 

  14. Kim HS, Oh SH, Kim JH, Kim JY, Kim DH, Lee SJ, Choi SU, Park KM, Ryoo ZY, Park TS, Lee S (2017) MLL–TET1 fusion protein promotes immortalization of myeloid progenitor cells and leukemia development. Haematologica 102:e434–e437

    Article  Google Scholar 

  15. Lee JW, Kim HS, Hwang J, Kim YH, Lim GY, Sohn WJ, Yoon SR, Kim JY, Park TS, Oh SH, Park KM, Choi SU, Ryoo ZY, Lee S (2012) Regulation of HOXA9 activity by predominant expression of DACH1 against C/EBPalpha and GATA-1 in myeloid leukemia with MLL-AF9. Biochem Biophys Res Commun 426:299–305

    Article  CAS  Google Scholar 

  16. Wouters BJ, Jorda MA, Keeshan K, Louwers I, Erpelinck-Verschueren CA, Tielemans D, Langerak AW, He Y, Yashiro-Ohtani Y, Zhang P et al (2007) Distinct gene expression profiles of acute myeloid/T-lymphoid leukemia with silenced CEBPA and mutations in NOTCH1. Blood 110:3706–3714

    Article  CAS  Google Scholar 

  17. Kirstetter P, Schuster MB, Bereshchenko O, Moore S, Dvinge H, Kurz E, Theilgaard-Monch K, Mansson R, Pedersen TA, Pabst T et al (2008) Modeling of C/EBPalpha mutant acute myeloid leukemia reveals a common expression signature of committed myeloid leukemia-initiating cells. Cancer Cell 13:299–310

    Article  CAS  Google Scholar 

  18. Kandilci A, Grosveld GC (2009) Reintroduction of CEBPA in MN1-overexpressing hematopoietic cells prevents their hyperproliferation and restores myeloid differentiation. Blood 114:1596–1606

    Article  CAS  Google Scholar 

  19. Thiel AT, Feng Z, Pant DK, Chodosh LA, Hua X (2013) The trithorax protein partner menin acts in tandem with EZH2 to suppress C/EBPalpha and differentiation in MLL-AF9 leukemia. Haematologica 98:918–927

    Article  CAS  Google Scholar 

  20. Kuo YH, Zaidi SK, Gornostaeva S, Komori T, Stein GS, Castilla LH (2009) Runx2 induces acute myeloid leukemia in cooperation with Cbfbeta-SMMHC in mice. Blood 113:3323–3332

    Article  CAS  Google Scholar 

  21. Keeshan K, He Y, Wouters BJ, Shestova O, Xu L, Sai H, Rodriguez CG, Maillard I, Tobias JW, Valk P, Carroll M, Aster JC, Delwel R, Pear WS (2006) Tribbles homolog 2 inactivates C/EBPalpha and causes acute myelogenous leukemia. Cancer Cell 10:401–411

    Article  CAS  Google Scholar 

  22. Benito JM, Godfrey L, Kojima K, Hogdal L, Wunderlich M, Geng H, Marzo I, Harutyunyan KG, Golfman L, North P, Kerry J, Ballabio E, Chonghaile TN, Gonzalo O, Qiu Y, Jeremias I, Debose LK, O’Brien E, Ma H, Zhou P, Jacamo R, Park E, Coombes KR, Zhang N, Thomas DA, O’Brien S, Kantarjian HM, Leverson JD, Kornblau SM, Andreeff M, Müschen M, Zweidler-McKay PA, Mulloy JC, Letai A, Milne TA, Konopleva M (2015) MLL-rearranged acute lymphoblastic leukemias activate BCL-2 through H3K79 methylation and are sensitive to the BCL-2-specific antagonist ABT-199. Cell Rep 13:2715–2727

    Article  CAS  Google Scholar 

  23. Cheng J, Blum R, Bowman C, Hu D, Shilatifard A, Shen S, Dynlacht BD (2014) A role for H3K4 monomethylation in gene repression and partitioning of chromatin readers. Mol Cell 53:979–992

    Article  CAS  Google Scholar 

  24. Argiropoulos B, Palmqvist L, Yung E, Kuchenbauer F, Heuser M, Sly LM, Wan A, Krystal G, Humphries RK (2008) Linkage of Meis1 leukemogenic activity to multiple downstream effectors including Trib2 and Ccl3. Exp Hematol 36:845–859

    Article  CAS  Google Scholar 

  25. Bernt KM, Zhu N, Sinha AU, Vempati S, Faber J, Krivtsov AV, Feng Z, Punt N, Daigle A, Bullinger L, Pollock RM, Richon VM, Kung AL, Armstrong SA (2011) MLL-rearranged leukemia is dependent on aberrant H3K79 methylation by DOT1L. Cancer Cell 20:66–78

    Article  CAS  Google Scholar 

  26. Okada Y, Feng Q, Lin Y, Jiang Q, Li Y, Coffield VM, Su L, Xu G, Zhang Y (2005) hDOT1L links histone methylation to leukemogenesis. Cell 121:167–178

    Article  CAS  Google Scholar 

  27. Koschmieder S, Halmos B, Levantini E, Tenen DG (2009) Dysregulation of the C/EBPalpha differentiation pathway in human cancer. J Clin Oncol 27:619–628

    Article  CAS  Google Scholar 

  28. Pabst T, Mueller BU, Harakawa N, Schoch C, Haferlach T, Behre G, Hiddemann W, Zhang DE, Tenen DG (2001) AML1-ETO downregulates the granulocytic differentiation factor C/EBPalpha in t(8;21) myeloid leukemia. Nat Med 7:444–451

    Article  CAS  Google Scholar 

  29. Perrotti D, Cesi V, Trotta R, Guerzoni C, Santilli G, Campbell K, Iervolino A, Condorelli F, Gambacorti-Passerini C, Caligiuri MA, Calabretta B (2002) BCR-ABL suppresses C/EBPalpha expression through inhibitory action of hnRNP E2. Nat Genet 30:48–58

    Article  CAS  Google Scholar 

  30. Zheng R, Friedman AD, Levis M, Li L, Weir EG, Small D (2004) Internal tandem duplication mutation of FLT3 blocks myeloid differentiation through suppression of C/EBPalpha expression. Blood 103:1883–1890

    Article  CAS  Google Scholar 

  31. Helbling D, Mueller BU, Timchenko NA, Schardt J, Eyer M, Betts DR, Jotterand M, Meyer-Monard S, Fey MF, Pabst T (2005) CBFB-SMMHC is correlated with increased calreticulin expression and suppresses the granulocytic differentiation factor CEBPA in AML with inv(16). Blood 106:1369–1375

    Article  CAS  Google Scholar 

  32. Gombart AF, Hofmann WK, Kawano S, Takeuchi S, Krug U, Kwok SH, Larsen RJ, Asou H, Miller CW, Hoelzer D et al (2002) Mutations in the gene encoding the transcription factor CCAAT/enhancer binding protein alpha in myelodysplastic syndromes and acute myeloid leukemias. Blood 99:1332–1340

    Article  CAS  Google Scholar 

  33. O'Connor C, Lohan F, Campos J, Ohlsson E, Salome M, Forde C, Artschwager R, Liskamp RM, Cahill MR, Kiely PA et al (2016) The presence of C/EBPalpha and its degradation are both required for TRIB2-mediated leukaemia. Oncogene 35:5272–5281

    Article  CAS  Google Scholar 

  34. Keeshan K, Shestova O, Ussin L, Pear WS (2008) Tribbles homolog 2 (Trib2) and HoxA9 cooperate to accelerate acute myelogenous leukemia. Blood Cells Mol Dis 40:119–121

    Article  CAS  Google Scholar 

  35. Stein SJ, Mack EA, Rome KS, Pajcini KV, Ohtani T, Xu L, Li Y, Meijerink JP, Faryabi RB, Pear WS (2016) Trib2 suppresses tumor initiation in notch-driven T-ALL. PLoS One 11:e0155408

    Article  Google Scholar 

  36. Matsushita H, Nakajima H, Nakamura Y, Tsukamoto H, Tanaka Y, Jin G, Yabe M, Asai S, Ono R, Nosaka T, Sugita K, Morimoto A, Hayashi Y, Hotta T, Ando K, Miyachi H (2008) C/EBPalpha and C/EBPvarepsilon induce the monocytic differentiation of myelomonocytic cells with the MLL-chimeric fusion gene. Oncogene 27:6749–6760

    Article  CAS  Google Scholar 

  37. Rishi L, Hannon M, Salome M, Hasemann M, Frank AK, Campos J, Timoney J, O'Connor C, Cahill MR, Porse B, Keeshan K (2014) Regulation of Trib2 by an E2F1-C/EBPalpha feedback loop in AML cell proliferation. Blood 123:2389–2400

    Article  CAS  Google Scholar 

  38. Jin SG, Wu X, Li AX, Pfeifer GP (2011) Genomic mapping of 5-hydroxymethylcytosine in the human brain. Nucleic Acids Res 39:5015–5024

    Article  CAS  Google Scholar 

  39. Yang H, Liu Y, Bai F, Zhang JY, Ma SH, Liu J, Xu ZD, Zhu HG, Ling ZQ, Ye D, Guan KL, Xiong Y (2013) Tumor development is associated with decrease of TET gene expression and 5-methylcytosine hydroxylation. Oncogene 32:663–669

    Article  CAS  Google Scholar 

  40. Chen Z, Shi X, Guo L, Li Y, Luo M, He J (2017) Decreased 5-hydroxymethylcytosine levels correlate with cancer progression and poor survival: a systematic review and meta-analysis. Oncotarget 8:1944–1952

    PubMed  Google Scholar 

  41. Tsuji M, Matsunaga H, Jinno D, Tsukamoto H, Suzuki N, Tomioka Y (2014) A validated quantitative liquid chromatography-tandem quadrupole mass spectrometry method for monitoring isotopologues to evaluate global modified cytosine ratios in genomic DNA. J Chromatogr B Anal Technol Biomed Life Sci 953-954:38–47

    Article  CAS  Google Scholar 

  42. Zanella F, Renner O, Garcia B, Callejas S, Dopazo A, Peregrina S, Carnero A, Link W (2010) Human TRIB2 is a repressor of FOXO that contributes to the malignant phenotype of melanoma cells. Oncogene 29:2973–2982

    Article  CAS  Google Scholar 

  43. Liang KL, O'Connor C, Veiga JP, McCarthy TV, Keeshan K (2016) TRIB2 regulates normal and stress-induced thymocyte proliferation. Cell Discov 2:15050

    Article  CAS  Google Scholar 

  44. Hill R, Madureira PA, Ferreira B, Baptista I, Machado S, Colaco L, Dos Santos M, Liu N, Dopazo A, Ugurel S et al (2017) TRIB2 confers resistance to anti-cancer therapy by activating the serine/threonine protein kinase AKT. Nat Commun 8:14687

    Article  Google Scholar 

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Acknowledgements

This work has supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (Grant No. NRF-2016R1C1B1010734 and NRF-2018R1D1A1B07049274).

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Authors and Affiliations

  1. School of Life Science, BK21 plus KNU Creative BioResearch Group, Kyungpook National University, Daegu, 41566, Republic of Korea

    Hyeng-Soo Kim, Ju-Heon Kim, Zae Young Ryoo & Sanggyu Lee

  2. Institute of Life Science and Biotechnology, Kyungpook National University, Daegu, 41566, Republic of Korea

    Hyeng-Soo Kim

  3. Department of Laboratory Medicine, College of Medicine, Inje University, Busan, 47392, Republic of Korea

    Seung Hwan Oh

  4. Department of Biochemistry, School of Dentistry, IHBR, Kyungpook National University, Daegu, 41940, Republic of Korea

    Wern-Joo Sohn & Jae-Young Kim

  5. Department of Physics, Kyungpook National University, Daegu, 41566, Republic of Korea

    Do-Hyung Kim

  6. Korea Research Institute of Chemical Technology, Daejeon, 34186, Republic of Korea

    Sang-Un Choi

  7. Department of Anatomy, Kyungpook National University School of Medicine, Daegu, 41944, Republic of Korea

    Kwon Moo Park

  8. Department of Laboratory Medicine, Kyung Hee University School of Medicine, Seoul, 02447, Republic of Korea

    Tae Sung Park

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  1. Hyeng-Soo Kim
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Correspondence to Sanggyu Lee.

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All animal studies were reviewed and approved by the Institutional Animal Care and Use Committee of Kyungpook National University.

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Kim, HS., Oh, S.H., Kim, JH. et al. TRIB2 regulates the differentiation of MLL–TET1 transduced myeloid progenitor cells. J Mol Med 96, 1267–1277 (2018). https://doi.org/10.1007/s00109-018-1700-3

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  • DOI: https://doi.org/10.1007/s00109-018-1700-3

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