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The multifaceted functions of C/EBPα in normal and malignant haematopoiesis

Leukemia volume 30, pages 767–775 (2016)Cite this article

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Abstract

The process of blood formation, haematopoiesis, depends upon a small number of haematopoietic stem cells (HSCs) that reside in the bone marrow. Differentiation of HSCs is characterised by decreased expression of genes associated with self-renewal accompanied by a stepwise activation of genes promoting differentiation. Lineage branching is further directed by groups of cooperating and counteracting genes forming complex networks of lineage-specific transcription factors. Imbalances in such networks can result in blockage of differentiation, lineage reprogramming and malignant transformation. CCAAT/enhancer-binding protein-α (C/EBPα) was originally identified 30 years ago as a transcription factor that binds both promoter and enhancer regions. Most of the early work focused on the role of C/EBPα in regulating transcriptional processes as well as on its functions in key differentiation processes during liver, adipogenic and haematopoietic development. Specifically, C/EBPα was shown to control differentiation by its ability to coordinate transcriptional output with cell cycle progression. Later, its role as an important tumour suppressor, mainly in acute myeloid leukaemia (AML), was recognised and has been the focus of intense studies by a number of investigators. More recent work has revisited the role of C/EBPα in normal haematopoiesis, especially its function in HSCs, and also started to provide more mechanistic insights into its role in normal and malignant haematopoiesis. In particular, the differential actions of C/EBPα isoforms, as well as its importance in chromatin remodelling and cellular reprogramming, are beginning to be elucidated. Finally, recent work has also shed light on the dichotomous function of C/EBPα in AML by demonstrating its ability to act as both a tumour suppressor and promoter. In the present review, we will summarise the current knowledge on the functions of C/EBPα during normal and malignant haematopoiesis with special emphasis on the recent work.

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References

  1. Ong CT, Corces VG . Enhancer function: new insights into the regulation of tissue-specific gene expression. Nat Rev Genet 2011; 12: 283–293.

    CAS  Google Scholar 

  2. Liber D, Domaschenz R, Holmqvist PH, Mazzarella L, Georgiou A, Leleu M et al. Epigenetic priming of a pre-B cell-specific enhancer through binding of Sox2 and Foxd3 at the ESC stage. Cell Stem Cell 2010; 7: 114–126.

    CAS  Google Scholar 

  3. Cai DH, Wang D, Keefer J, Yeamans C, Hensley K, Friedman AD . C/EBP alpha:AP-1 leucine zipper heterodimers bind novel DNA elements, activate the PU.1 promoter and direct monocyte lineage commitment more potently than C/EBP alpha homodimers or AP-1. Oncogene 2008; 27: 2772–2779.

    CAS  Google Scholar 

  4. Hattori T, Ohoka N, Inoue Y, Hayashi H, Onozaki K . C/EBP family transcription factors are degraded by the proteasome but stabilized by forming dimer. Oncogene 2003; 22: 1273–1280.

    CAS  Google Scholar 

  5. Ramji DP, Foka P . CCAAT/enhancer-binding proteins: structure, function and regulation. Biochem J 2002; 365: 561–575.

    CAS  Google Scholar 

  6. Miller M, Shuman JD, Sebastian T, Dauter Z, Johnson PF . Structural basis for DNA recognition by the basic region leucine zipper transcription factor CCAAT/enhancer-binding protein alpha. J Biol Chem 2003; 278: 15178–15184.

    CAS  Google Scholar 

  7. Nerlov C, Ziff EB . CCAAT/enhancer binding protein-alpha amino acid motifs with dual TBP and TFIIB binding ability co-operate to activate transcription in both yeast and mammalian cells. EMBO J 1995; 14: 4318–4328.

    CAS  Google Scholar 

  8. Johansen LM, Iwama A, Lodie TA, Sasaki K, Felsher DW, Golub TR et al. c-Myc is a critical target for c/EBPalpha in granulopoiesis. Mol Cell Biol 2001; 21: 3789–3806.

    CAS  Google Scholar 

  9. Porse BT, Pedersen TA, Xu X, Lindberg B, Wewer UM, Friis-Hansen L et al. E2F repression by C/EBPalpha is required for adipogenesis and granulopoiesis in vivo. Cell 2001; 107: 247–258.

    CAS  Google Scholar 

  10. Slomiany BA, D’Arigo KL, Kelly MM, Kurtz DT . C/EBPalpha inhibits cell growth via direct repression of E2F-DP-mediated transcription. Mol Cell Biol 2000; 20: 5986–5997.

    CAS  Google Scholar 

  11. Calkhoven CF, Muller C, Leutz A . Translational control of C/EBPalpha and C/EBPbeta isoform expression. Genes Dev 2000; 14: 1920–1932.

    CAS  Google Scholar 

  12. Timchenko NA, Wilde M, Nakanishi M, Smith JR, Darlington GJ . CCAAT/enhancer-binding protein alpha (C/EBP alpha) inhibits cell proliferation through the p21 (WAF-1/CIP-1/SDI-1) protein. Genes Dev 1996; 10: 804–815.

    CAS  Google Scholar 

  13. Muller C, Calkhoven CF, Sha X, Leutz A . The CCAAT enhancer-binding protein alpha (C/EBPalpha) requires a SWI/SNF complex for proliferation arrest. J Biol Chem 2004; 279: 7353–7358.

    Google Scholar 

  14. Wang H, Iakova P, Wilde M, Welm A, Goode T, Roesler WJ et al. C/EBPalpha arrests cell proliferation through direct inhibition of Cdk2 and Cdk4. Mol Cell 2001; 8: 817–828.

    CAS  Google Scholar 

  15. Schuster MB, Porse BT . C/EBPalpha: a tumour suppressor in multiple tissues? Biochim Biophys Acta 2006; 1766: 88–103.

    CAS  Google Scholar 

  16. Wang ND, Finegold MJ, Bradley A, Ou CN, Abdelsayed SV, Wilde MD et al. Impaired energy homeostasis in C/EBP alpha knockout mice. Science 1995; 269: 1108–1112.

    CAS  Google Scholar 

  17. Zhang DE, Zhang P, Wang ND, Hetherington CJ, Darlington GJ, Tenen DG . Absence of granulocyte colony-stimulating factor signaling and neutrophil development in CCAAT enhancer binding protein alpha-deficient mice. Proc Natl Acad Sci USA 1997; 94: 569–574.

    CAS  Google Scholar 

  18. Zhang P, Iwasaki-Arai J, Iwasaki H, Fenyus ML, Dayaram T, Owens BM et al. Enhancement of hematopoietic stem cell repopulating capacity and self-renewal in the absence of the transcription factor C/EBP alpha. Immunity 2004; 21: 853–863.

    CAS  Google Scholar 

  19. Friedman AD . C/EBPalpha in normal and malignant myelopoiesis. Int J Hematol 2015; 101: 330–341.

    CAS  Google Scholar 

  20. Back J, Allman D, Chan S, Kastner P . Visualizing PU.1 activity during hematopoiesis. Exp Hematol 2005; 33: 395–402.

    CAS  Google Scholar 

  21. DeKoter RP, Singh H . Regulation of B lymphocyte and macrophage development by graded expression of PU.1. Science 2000; 288: 1439–1441.

    CAS  Google Scholar 

  22. Okuda T, van Deursen J, Hiebert SW, Grosveld G, Downing JR . AML1, the target of multiple chromosomal translocations in human leukemia, is essential for normal fetal liver hematopoiesis. Cell 1996; 84: 321–330.

    Article  CAS  Google Scholar 

  23. Tamura T, Thotakura P, Tanaka TS, Ko MS, Ozato K . Identification of target genes and a unique cis element regulated by IRF-8 in developing macrophages. Blood 2005; 106: 1938–1947.

    CAS  Google Scholar 

  24. Hock H, Hamblen MJ, Rooke HM, Traver D, Bronson RT, Cameron S et al. Intrinsic requirement for zinc finger transcription factor Gfi-1 in neutrophil differentiation. Immunity 2003; 18: 109–120.

    CAS  Google Scholar 

  25. Shivdasani RA, Mayer EL, Orkin SH . Absence of blood formation in mice lacking the T-cell leukaemia oncoprotein tal-1/SCL. Nature 1995; 373: 432–434.

    CAS  Google Scholar 

  26. Rieger MA, Hoppe PS, Smejkal BM, Eitelhuber AC, Schroeder T . Hematopoietic cytokines can instruct lineage choice. Science 2009; 325: 217–218.

    CAS  Google Scholar 

  27. Heinz S, Benner C, Spann N, Bertolino E, Lin YC, Laslo P et al. Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities. Mol Cell 2010; 38: 576–589.

    CAS  Google Scholar 

  28. Kummalue T, Friedman AD . Cross-talk between regulators of myeloid development: C/EBPalpha binds and activates the promoter of the PU.1 gene. J Leukocyte Biol 2003; 74: 464–470.

    CAS  Google Scholar 

  29. Yeamans C, Wang D, Paz-Priel I, Torbett BE, Tenen DG, Friedman AD . C/EBPalpha binds and activates the PU.1 distal enhancer to induce monocyte lineage commitment. Blood 2007; 110: 3136–3142.

    CAS  Google Scholar 

  30. Reddy VA, Iwama A, Iotzova G, Schulz M, Elsasser A, Vangala RK et al. Granulocyte inducer C/EBPalpha inactivates the myeloid master regulator PU.1: possible role in lineage commitment decisions. Blood 2002; 100: 483–490.

    CAS  Google Scholar 

  31. Dahl R, Walsh JC, Lancki D, Laslo P, Iyer SR, Singh H et al. Regulation of macrophage and neutrophil cell fates by the PU.1:C/EBPalpha ratio and granulocyte colony-stimulating factor. Nat Immunol 2003; 4: 1029–1036.

    Article  CAS  Google Scholar 

  32. Behre G, Singh SM, Liu H, Bortolin LT, Christopeit M, Radomska HS et al. Ras signaling enhances the activity of C/EBP alpha to induce granulocytic differentiation by phosphorylation of serine 248. J Biol Chem 2002; 277: 26293–26299.

    CAS  Google Scholar 

  33. Hasemann MS, Schuster MB, Frank AK, Theilgaard-Monch K, Pedersen TA, Nerlov C et al. Phosphorylation of serine 248 of C/EBPalpha is dispensable for myelopoiesis but its disruption leads to a low penetrant myeloid disorder with long latency. PLoS One 2012; 7: e38841.

    CAS  Google Scholar 

  34. Radomska HS, Huettner CS, Zhang P, Cheng T, Scadden DT, Tenen DG . CCAAT/enhancer binding protein alpha is a regulatory switch sufficient for induction of granulocytic development from bipotential myeloid progenitors. Mol Cell Biol 1998; 18: 4301–4314.

    CAS  Google Scholar 

  35. Wang D, D’Costa J, Civin CI, Friedman AD . C/EBPalpha directs monocytic commitment of primary myeloid progenitors. Blood 2006; 108: 1223–1229.

    CAS  Google Scholar 

  36. Xie H, Ye M, Feng R, Graf T . Stepwise reprogramming of B cells into macrophages. Cell 2004; 117: 663–676.

    CAS  Google Scholar 

  37. Hsu CL, King-Fleischman AG, Lai AY, Matsumoto Y, Weissman IL, Kondo M . Antagonistic effect of CCAAT enhancer-binding protein-alpha and Pax5 in myeloid or lymphoid lineage choice in common lymphoid progenitors. Proc Natl Acad Sci USA 2006; 103: 672–677.

    CAS  Google Scholar 

  38. Ye M, Zhang H, Amabile G, Yang H, Staber PB, Zhang P et al. C/EBPa controls acquisition and maintenance of adult haematopoietic stem cell quiescence. Nat Cell Biol 2013; 15: 385–394.

    CAS  Google Scholar 

  39. Hasemann MS, Lauridsen FK, Waage J, Jakobsen JS, Frank AK, Schuster MB et al. C/EBPalpha is required for long-term self-renewal and lineage priming of hematopoietic stem cells and for the maintenance of epigenetic configurations in multipotent progenitors. PLoS Genet 2014; 10: e1004079.

    Google Scholar 

  40. Guo H, Ma O, Friedman AD . The Cebpa +37-kb enhancer directs transgene expression to myeloid progenitors and to long-term hematopoietic stem cells. J Leukoc Biol 2014; 96: 419–426.

    Google Scholar 

  41. Wolfler A, Danen-van Oorschot AA, Haanstra JR, Valkhof M, Bodner C, Vroegindeweij E et al. Lineage-instructive function of C/EBPalpha in multipotent hematopoietic cells and early thymic progenitors. Blood 2010; 116: 4116–4125.

    Google Scholar 

  42. Essers MA, Offner S, Blanco-Bose WE, Waibler Z, Kalinke U, Duchosal MA et al. IFNalpha activates dormant haematopoietic stem cells in vivo. Nature 2009; 458: 904–908.

    CAS  Google Scholar 

  43. Shih AH, Abdel-Wahab O, Patel JP, Levine RL . The role of mutations in epigenetic regulators in myeloid malignancies. Nat Rev Cancer 2012; 12: 599–612.

    CAS  Google Scholar 

  44. Abdel-Wahab O, Levine RL . Mutations in epigenetic modifiers in the pathogenesis and therapy of acute myeloid leukemia. Blood 2013; 121: 3563–3572.

    CAS  Google Scholar 

  45. Pabst T, Mueller BU, Zhang P, Radomska HS, Narravula S, Schnittger S et al. Dominant-negative mutations of CEBPA, encoding CCAAT/enhancer binding protein-alpha (C/EBPalpha), in acute myeloid leukemia. Nat Genet 2001; 27: 263–270.

    CAS  Google Scholar 

  46. Leroy H, Roumier C, Huyghe P, Biggio V, Fenaux P, Preudhomme C . CEBPA point mutations in hematological malignancies. Leukemia 2005; 19: 329–334.

    CAS  Google Scholar 

  47. Schlenk RF, Dohner K, Kneba M, Gotze K, Hartmann F, Del Valle F et al. Gene mutations and response to treatment with all-trans retinoic acid in elderly patients with acute myeloid leukemia. Results from the AMLSG Trial AML HD98B. Haematologica 2009; 94: 54–60.

    CAS  Google Scholar 

  48. Schlenk RF, Dohner K, Krauter J, Frohling S, Corbacioglu A, Bullinger L et al. Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N Engl J Med 2008; 358: 1909–1918.

    CAS  Google Scholar 

  49. Patel JP, Gonen M, Figueroa ME, Fernandez H, Sun Z, Racevskis J et al. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med 2012; 366: 1079–1089.

    CAS  Google Scholar 

  50. Benthaus T, Schneider F, Mellert G, Zellmeier E, Schneider S, Kakadia PM et al. Rapid and sensitive screening for CEBPA mutations in acute myeloid leukaemia. Br J Haematol 2008; 143: 230–239.

    CAS  Google Scholar 

  51. Diaz-Beya M, Brunet S, Nomdedeu J, Tejero R, Diaz T, Pratcorona M et al. MicroRNA expression at diagnosis adds relevant prognostic information to molecular categorization in patients with intermediate-risk cytogenetic acute myeloid leukemia. Leukemia 2014; 28: 804–812.

    CAS  Google Scholar 

  52. Hollink IH, van den Heuvel-Eibrink MM, Arentsen-Peters ST, Zimmermann M, Peeters JK, Valk PJ et al. Characterization of CEBPA mutations and promoter hypermethylation in pediatric acute myeloid leukemia. Haematologica 2011; 96: 384–392.

    CAS  Google Scholar 

  53. Frohling S, Schlenk RF, Stolze I, Bihlmayr J, Benner A, Kreitmeier S et al. Mutations in younger adults with acute myeloid leukemia and normal cytogenetics: prognostic relevance and analysis of cooperating mutations. J Clin Oncol 2004; 22: 624–633.

    Google Scholar 

  54. Fasan A, Haferlach C, Alpermann T, Jeromin S, Grossmann V, Eder C et al. The role of different genetic subtypes of CEBPA mutated AML. Leukemia 2014; 28: 794–803.

    CAS  Google Scholar 

  55. Preudhomme C, Sagot C, Boissel N, Cayuela JM, Tigaud I, de Botton S et al. Favorable prognostic significance of CEBPA mutations in patients with de novo acute myeloid leukemia: a study from the Acute Leukemia French Association (ALFA). Blood 2002; 100: 2717–2723.

    CAS  Google Scholar 

  56. Gombart AF, Hofmann WK, Kawano S, Takeuchi S, Krug U, Kwok SH et al. Mutations in the gene encoding the transcription factor CCAAT/enhancer binding protein alpha in myelodysplastic syndromes and acute myeloid leukemias. Blood 2002; 99: 1332–1340.

    CAS  Google Scholar 

  57. Landschulz WH, Johnson PF, McKnight SL . The DNA binding domain of the rat liver nuclear protein C/EBP is bipartite. Science 1989; 243: 1681–1688.

    CAS  Google Scholar 

  58. Dufour A, Schneider F, Metzeler KH, Hoster E, Schneider S, Zellmeier E et al. Acute myeloid leukemia with biallelic CEBPA gene mutations and normal karyotype represents a distinct genetic entity associated with a favorable clinical outcome. J Clin Oncol 2010; 28: 570–577.

    CAS  Google Scholar 

  59. Pabst T, Eyholzer M, Fos J, Mueller BU . Heterogeneity within AML with CEBPA mutations; only CEBPA double mutations, but not single CEBPA mutations are associated with favourable prognosis. Br J Cancer 2009; 100: 1343–1346.

    CAS  Google Scholar 

  60. Rapin N, Bagger FO, Jendholm J, Mora-Jensen H, Krogh A, Kohlmann A et al. Comparing cancer vs normal gene expression profiles identifies new disease entities and common transcriptional programs in AML patients. Blood 2014; 123: 894–904.

    CAS  Google Scholar 

  61. Vardiman JW, Thiele J, Arber DA, Brunning RD, Borowitz MJ, Porwit A et al. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood 2009; 114: 937–951.

    CAS  Google Scholar 

  62. Wouters BJ, Lowenberg B, Erpelinck-Verschueren CA, van Putten WL, Valk PJ, Delwel R . Double CEBPA mutations, but not single CEBPA mutations, define a subgroup of acute myeloid leukemia with a distinctive gene expression profile that is uniquely associated with a favorable outcome. Blood 2009; 113: 3088–3091.

    CAS  Google Scholar 

  63. Smith ML, Cavenagh JD, Lister TA, Fitzgibbon J . Mutation of CEBPA in familial acute myeloid leukemia. N Engl J Med 2004; 351: 2403–2407.

    CAS  Google Scholar 

  64. Green CL, Tawana K, Hills RK, Bodor C, Fitzgibbon J, Inglott S et al. GATA2 mutations in sporadic and familial acute myeloid leukaemia patients with CEBPA mutations. Br J Haematol 2013; 161: 701–705.

    CAS  Google Scholar 

  65. Fasan A, Alpermann T, Haferlach C, Grossmann V, Roller A, Kohlmann A et al. Frequency and prognostic impact of CEBPA proximal, distal and core promoter methylation in normal karyotype AML: a study on 623 cases. PLoS One 2013; 8: e54365.

    CAS  Google Scholar 

  66. Zhang H, Alberich-Jorda M, Amabile G, Yang H, Staber PB, Di Ruscio A et al. Sox4 is a key oncogenic target in C/EBPalpha mutant acute myeloid leukemia. Cancer Cell 2013; 24: 575–588.

    CAS  Google Scholar 

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

    CAS  Google Scholar 

  68. Ptasinska A, Assi SA, Martinez-Soria N, Imperato MR, Piper J, Cauchy P et al. Identification of a dynamic core transcriptional network in t(8;21) AML that regulates differentiation block and self-renewal. Cell Rep 2014; 8: 1974–1988.

    CAS  Google Scholar 

  69. Helbling D, Mueller BU, Timchenko NA, Hagemeijer A, Jotterand M, Meyer-Monard S et al. The leukemic fusion gene AML1-MDS1-EVI1 suppresses CEBPA in acute myeloid leukemia by activation of Calreticulin. Proc Natl Acad Sci USA 2004; 101: 13312–13317.

    CAS  Google Scholar 

  70. Helbling D, Mueller BU, Timchenko NA, Schardt J, Eyer M, Betts DR et al. CBFB-SMMHC is correlated with increased calreticulin expression and suppresses the granulocytic differentiation factor CEBPA in AML with inv(16). Blood 2005; 106: 1369–1375.

    CAS  Google Scholar 

  71. Perrotti D, Cesi V, Trotta R, Guerzoni C, Santilli G, Campbell K et al. BCR-ABL suppresses C/EBPalpha expression through inhibitory action of hnRNP E2. Nat Genet 2002; 30: 48–58.

    CAS  Google Scholar 

  72. Perrotti D, Calabretta B . Post-transcriptional mechanisms in BCR/ABL leukemogenesis: role of shuttling RNA-binding proteins. Oncogene 2002; 21: 8577–8583.

    CAS  Google Scholar 

  73. Mueller BU, Pabst T . C/EBPalpha and the pathophysiology of acute myeloid leukemia. Curr Opin Hematol 2006; 13: 7–14.

    Google Scholar 

  74. Keeshan K, He Y, Wouters BJ, Shestova O, Xu L, Sai H et al. Tribbles homolog 2 inactivates C/EBPalpha and causes acute myelogenous leukemia. Cancer Cell 2006; 10: 401–411.

    CAS  Google Scholar 

  75. Wouters BJ, Jorda MA, Keeshan K, Louwers I, Erpelinck-Verschueren CA, Tielemans D et al. Distinct gene expression profiles of acute myeloid/T-lymphoid leukemia with silenced CEBPA and mutations in NOTCH1. Blood 2007; 110: 3706–3714.

    CAS  Google Scholar 

  76. Dedhia PH, Keeshan K, Uljon S, Xu L, Vega ME, Shestova O et al. Differential ability of Tribbles family members to promote degradation of C/EBPalpha and induce acute myelogenous leukemia. Blood 2010; 116: 1321–1328.

    CAS  Google Scholar 

  77. Nerlov C . C/EBPalpha mutations in acute myeloid leukaemias. Nat Rev Cancer 2004; 4: 394–400.

    CAS  Google Scholar 

  78. Zhang P, Iwasaki-Arai J, Iwasaki H, Fenyus ML, Dayaram T, Owens BM et al. Enhancement of hematopoietic stem cell repopulating capacity and self-renewal in the absence of the transcription factor C/EBPalpha. Immunity 2004; 21: 853–863.

    CAS  Google Scholar 

  79. Wagner K, Zhang P, Rosenbauer F, Drescher B, Kobayashi S, Radomska HS et al. Absence of the transcription factor CCAAT enhancer binding protein alpha results in loss of myeloid identity in bcr/abl-induced malignancy. Proc Natl Acad Sci USA 2006; 103: 6338–6343.

    CAS  Google Scholar 

  80. Ohlsson E, Hasemann MS, Willer A, Lauridsen FK, Rapin N, Jendholm J et al. Initiation of MLL-rearranged AML is dependent on C/EBPalpha. J Exp Med 2014; 211: 5–13.

    CAS  Google Scholar 

  81. Ye M, Zhang H, Yang H, Koche R, Staber PB, Cusan M et al. Hematopoietic differentiation is required for initiation of acute myeloid leukemia. Cell Stem Cell 2015; 17: 611–623.

    CAS  Google Scholar 

  82. Hirai H, Zhang P, Dayaram T, Hetherington CJ, Mizuno S, Imanishi J et al. C/EBPbeta is required for ‘emergency’ granulopoiesis. Nat Immunol 2006; 7: 732–739.

    CAS  Google Scholar 

  83. Jones LC, Lin ML, Chen SS, Krug U, Hofmann WK, Lee S et al. Expression of C/EBPbeta from the C/ebpalpha gene locus is sufficient for normal hematopoiesis in vivo. Blood 2002; 99: 2032–2036.

    CAS  Google Scholar 

  84. Collins C, Wang J, Miao H, Bronstein J, Nawer H, Xu T et al. C/EBPalpha is an essential collaborator in Hoxa9/Meis1-mediated leukemogenesis. Proc Natl Acad Sci USA 2014; 111: 9899–9904.

    CAS  Google Scholar 

  85. Madsen MS, Siersbaek R, Boergesen M, Nielsen R, Mandrup S . Peroxisome proliferator-activated receptor gamma and C/EBPalpha synergistically activate key metabolic adipocyte genes by assisted loading. Mol Cell Biol 2014; 34: 939–954.

    Google Scholar 

  86. Pedersen TA, Kowenz-Leutz E, Leutz A, Nerlov C . Cooperation between C/EBPalpha TBP/TFIIB and SWI/SNF recruiting domains is required for adipocyte differentiation. Genes Dev 2001; 15: 3208–3216.

    CAS  Google Scholar 

  87. Porse BT, Bryder D, Theilgaard-Monch K, Hasemann MS, Anderson K, Damgaard I et al. Loss of C/EBP alpha cell cycle control increases myeloid progenitor proliferation and transforms the neutrophil granulocyte lineage. J Exp Med 2005; 202: 85–96.

    CAS  Google Scholar 

  88. Kirstetter P, Schuster MB, Bereshchenko O, Moore S, Dvinge H, Kurz E et al. Modeling of C/EBPalpha mutant acute myeloid leukemia reveals a common expression signature of committed myeloid leukemia-initiating cells. Cancer Cell 2008; 13: 299–310.

    CAS  Google Scholar 

  89. Krivtsov AV, Twomey D, Feng Z, Stubbs MC, Wang Y, Faber J et al. Transformation from committed progenitor to leukaemia stem cell initiated by MLL-AF9. Nature 2006; 442: 818–822.

    CAS  Google Scholar 

  90. Reya T, Morrison SJ, Clarke MF, Weissman IL . Stem cells, cancer, and cancer stem cells. Nature 2001; 414: 105–111.

    CAS  Google Scholar 

  91. Shlush LI, Zandi S, Mitchell A, Chen WC, Brandwein JM, Gupta V et al. Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia. Nature 2014; 506: 328–333.

    CAS  Google Scholar 

  92. Mora-Jensen H, Jendholm J, Rapin N, Andersen MK, Roug AS, Bagger FO et al. Cellular origin of prognostic chromosomal aberrations in AML patients. Leukemia 2015; 29: 1785–1789.

    CAS  Google Scholar 

  93. Bereshchenko O, Mancini E, Moore S, Bilbao D, Mansson R, Luc S et al. Hematopoietic stem cell expansion precedes the generation of committed myeloid leukemia-initiating cells in C/EBPalpha mutant AML. Cancer Cell 2009; 16: 390–400.

    CAS  Google Scholar 

  94. Kato N, Kitaura J, Doki N, Komeno Y, Watanabe-Okochi N, Togami K et al. Two types of C/EBPalpha mutations play distinct but collaborative roles in leukemogenesis: lessons from clinical data and BMT models. Blood 2011; 117: 221–233.

    CAS  Google Scholar 

  95. Reckzeh K, Bereshchenko O, Mead A, Rehn M, Kharazi S, Jacobsen SE et al. Molecular and cellular effects of oncogene cooperation in a genetically accurate AML mouse model. Leukemia 2012; 26: 1527–1536.

    CAS  Google Scholar 

  96. Alberich-Jorda M, Wouters B, Balastik M, Shapiro-Koss C, Zhang H, Di Ruscio A et al. C/EBPgamma deregulation results in differentiation arrest in acute myeloid leukemia. J Clin Invest 2012; 122: 4490–4504.

    CAS  Google Scholar 

  97. Togami K, Kitaura J, Uchida T, Inoue D, Nishimura K, Kawabata KC et al. A C-terminal mutant of CCAAT-enhancer-binding protein alpha (C/EBPalpha-Cm) downregulates Csf1r, a potent accelerator in the progression of acute myeloid leukemia with C/EBPalpha-Cm. Exp Hematol 2015; 43: 300–308, e301.

    CAS  Google Scholar 

  98. Grebien F, Vedadi M, Getlik M, Giambruno R, Grover A, Avellino R et al. Pharmacological targeting of the Wdr5-MLL interaction in C/EBPalpha N-terminal leukemia. Nat Chem Biol 2015; 11: 571–578.

    CAS  Google Scholar 

  99. Laiosa CV, Stadtfeld M, Xie H, de Andres-Aguayo L, Graf T . Reprogramming of committed T cell progenitors to macrophages and dendritic cells by C/EBP alpha and PU.1 transcription factors. Immunity 2006; 25: 731–744.

    CAS  Google Scholar 

  100. Di Stefano B, Sardina JL, van Oevelen C, Collombet S, Kallin EM, Vicent GP et al. C/EBPalpha poises B cells for rapid reprogramming into induced pluripotent stem cells. Nature 2014; 506: 235–239.

    CAS  Google Scholar 

  101. Kallin EM, Rodriguez-Ubreva J, Christensen J, Cimmino L, Aifantis I, Helin K et al. Tet2 facilitates the derepression of myeloid target genes during CEBPalpha-induced transdifferentiation of pre-B cells. Mol Cell 2012; 48: 266–276.

    CAS  Google Scholar 

  102. Hanna J, Markoulaki S, Schorderet P, Carey BW, Beard C, Wernig M et al. Direct reprogramming of terminally differentiated mature B lymphocytes to pluripotency. Cell 2008; 133: 250–264.

    CAS  Google Scholar 

  103. Bagger FO, Rapin N, Theilgaard-Monch K, Kaczkowski B, Thoren LA, Jendholm J et al. HemaExplorer: a database of mRNA expression profiles in normal and malignant haematopoiesis. Nucleic Acids Res 2013; 41: D1034–D1039.

    CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from the Danish Council for Strategic Research, the Danish Cancer Society and through a centre grant from the Novo Nordisk Foundation Section for Stem Cell Biology in Human Disease. We thank Geer Rift for help with the illustrations.

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  1. E Ohlsson

    Present address: 4Current address: The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.,

Authors and Affiliations

  1. The Finsen Laboratory/Rigshospitalet, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark

    E Ohlsson, M B Schuster, M Hasemann & B T Porse

  2. Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark

    E Ohlsson, M B Schuster, M Hasemann & B T Porse

  3. Danish Stem Cell Centre (DanStem), Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark

    E Ohlsson, M B Schuster, M Hasemann & B T Porse

Authors
  1. E Ohlsson
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  2. M B Schuster
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  3. M Hasemann
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  4. B T Porse
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Corresponding author

Correspondence to B T Porse.

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Ohlsson, E., Schuster, M., Hasemann, M. et al. The multifaceted functions of C/EBPα in normal and malignant haematopoiesis. Leukemia 30, 767–775 (2016). https://doi.org/10.1038/leu.2015.324

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  • DOI: https://doi.org/10.1038/leu.2015.324

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