C/EBPα in normal and malignant myelopoiesis

International Journal of Hematology

Volumn 101, Issue 4, 2015, Pages 330-341

  Friedman, Alan D ^a  

^a JOHNS HOPKINS UNIVERSITY   (United States)

Author keywords

Acute myeloid leukemia (AML); C EBP ; Differentiation; Myeloid

Indexed keywords

CCAAT ENHANCER BINDING PROTEIN; CCAAT ENHANCER BINDING PROTEIN ALPHA; CEBPA PROTEIN, HUMAN; MICRORNA; TRANSCRIPTION FACTOR RUNX1;

ACUTE MYELOBLASTIC LEUKEMIA; ANIMAL; GENE EXPRESSION REGULATION; GENETICS; HUMAN; METABOLISM; MUTATION; MYELOPOIESIS; PATHOLOGY; PROTEIN PROCESSING;

ANIMALS; CCAAT-ENHANCER-BINDING PROTEIN-ALPHA; CCAAT-ENHANCER-BINDING PROTEINS; CORE BINDING FACTOR ALPHA 2 SUBUNIT; GENE EXPRESSION REGULATION, DEVELOPMENTAL; GENE EXPRESSION REGULATION, LEUKEMIC; HUMANS; LEUKEMIA, MYELOID, ACUTE; MICRORNAS; MUTATION; MYELOPOIESIS; PROTEIN PROCESSING, POST-TRANSLATIONAL;

EID: 84939938017     PISSN: 09255710     EISSN: 18653774     Source Type: Journal    
DOI: 10.1007/s12185-015-1764-6     Document Type: Review

References (153)

1. Graves BJ, Johnson PF, McKnight SL. Homologous recognition of a promoter domain common to the MSV LTR and the HSV tk gene. Cell. 1986;44:565–76.
2. Johnson PF, Landschulz WH, Graves BJ, McKnight SL. Identification of a rat liver nuclear protein that binds to the enhancer core element of three animal viruses. Genes Dev. 1987;1:133–46.
3. Landschulz WH, Johnson PF, Adashi EY, Graves BJ, McKnight SL. Isolation of a recombinant copy of the gene encoding C/EBP. Genes Dev. 1988;2:786–800.
4. Landschulz WH, Johnson PF, McKnight SL. The leucine zipper: a hypothetical structure common to a new class of DNA binding proteins. Science. 1988;240:1759–64.
5. Landschulz WH, Johnson PF, McKnight SL. The DNA binding domain of the rat liver nuclear protein C/EBP is bipartite. Science. 1989;243:1681–8.
6. Agre P, Johnson PF, McKnight SL. Cognate DNA binding specificity retained after leucine zipper exchange between GCN4 and C/EBP. Science. 1989;246:922–6.
7. Vinson CR, Sigler PB, McKnight SL. Scissors-grip model for DNA recognition by a family of leucine zipper proteins. Science. 1989;246:911–6.
8. 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 α. J Biol Chem. 2003;278:15178–84.
9. Friedman AD, McKnight SL. Identification of two polypeptide segments of CCAAT/enhancer-binding protein required for transcriptional activation of the serum albumin gene. Genes Dev. 1990;4:1416–26.
10. Williams SC, Angerer ND, Johnson PF. C/EBP proteins contain nuclear localization signals imbedded in their basic regions. Gene Expr. 1997;6:371–85.
11. Friedman AD, Landschulz WH, McKnight SL. CCAAT/enhancer binding protein activates the promoter of the serum albumin gene in cultured hepatoma cells. Genes Dev. 1989;3:1314–22.
12. Nerlov C, Ziff EB. Three levels of functional interaction determine the activity of CCAAT/enhancer binding protein-α on the serum albumin promoter. Genes Dev. 1994;8:350–62.
13. Pedersen TA, Kowenz-Leutz E, Leutz A, Nerlov C. Cooperation between C/EBPα TBP/TFIIB and SWI/SNF recruiting domains is required for adipocyte differentiation. Genes Dev. 2001;15:3208–16.
14. Bararia D, Trivedi AK, Zada AA, Greif PA, Mulaw MA, Christopeit M, et al. Proteomic identification of the MYST domain histone acetyltransferase TIP60 (HTATIP) as a co-activator of the myeloid transcription factor C/EBPα. Leukemia. 2008;22:800–7.
15. Koleva RI, Ficarro SB, Radomska HS, Carrasco-Alfonso MJ, Alberta JA, Webber JT, et al. C/EBPα and DEK coordinately regulate myeloid differentiation. Blood. 2012;119:4878–88.
16. Porse BT, Pedersen TA, Xu X, Lindberg B, Wewer UM, Friis-Hansen L, et al. E2F repression by C/EBPα is required for adipogenesis and granulopoiesis in vivo. Cell. 2001;107:247–58.
17. Johansen LM, Iwama A, Lodie TA, Sasaki K, Felsher DW, Golub TR, et al. G. c-Myc is a critical target for C/EBPα in granulopoiesis. Mol Cell Biol. 2001;21:3789–806.
18. Paz-Priel I, Cai DH, Wang D, Kowalski J, Blackford A, Liu H, et al. CCAAT/enhancer binding protein α (C/EBPα) and C/EBPα myeloid oncoproteins induce bcl-2 via interaction of their basic regions with nuclear factor-κB p50. Mol Cancer Res. 2005;3:585–96.
19. Paz-Priel I, Ghosal AK, Kowalski J, Friedman AD. C/EBPα or C/EBPα oncoproteins regulate the intrinsic and extrinsic apoptotic pathways by direct interaction with NF-κB p50 bound to the bcl-2 and FLIP gene promoters. Leukemia. 2009;23:365–74.
20. Paz-Priel I, Houng S, Dooher J, Friedman AD. C/EBPα and C/EBPα oncoproteins regulate nfkb1 and displace histone deacetylases from NF-κB p50 homodimers to induce NF-κB target genes. Blood. 2011;117:4085–94.
21. Cao Z, Umek RM, McKnight SL. Regulated expression of three C/EBP isoforms during adipose conversion of 3T3-L1 cells. Genes Dev. 1991;5:1538–52.
22. Williams SC, Cantwell CA, Johnson PF. A family of C/EBP-related proteins capable of forming covalently linked leucine zipper dimers in vitro. Genes Dev. 1991;5:1553–67.
23. Kataoka K, Noda M, Nishizawa M. Maf nuclear oncoprotein recognizes sequences related to an AP-1 site and forms heterodimers with both Fos and Jun. Mol Cell Biol. 1994;14:700–12.
24. Vinson CR, Hai T, Boyd SM. Dimerization specificity of the leucine zipper-containing bZIP motif on DNA binding: prediction and rational design. Genes Dev. 1993;7:1047–58.
25. Cai DH, Wang D, Keefer J, Yeamans C, Hensley K, Friedman AD. C/EBPα:AP-1 leucine zipper heterodimers bind novel DNA elements, activate the PU.1 promoter and direct monocyte lineage commitment more potently than C/EBPα homodimers or AP-1. Oncogene. 2008;27:2772–9.
26. Hong S, Skaist AM, Wheelan SJ, Friedman AD. AP-1 protein induction during monopoiesis favors C/EBP: AP-1 heterodimers over C/EBP homodimerization and stimulates FosB transcription. J Leukoc Biol. 2011;90:643–51.
27. Shuman JD, Cheong J, Coligan JE. ATF-2 and C/EBPα can form a heterodimeric DNA binding complex in vitro. Functional implications for transcriptional regulation. J Biol Chem. 1997;272:12793–800.
28. Descombes P, Schibler U. A liver-enriched transcriptional activator protein, LAP, and a transcriptional inhibitory protein, LIP, are translated from the same mRNA. Cell. 1991;67:569–79.
29. Lin FT, MacDougald OA, Diehl AM, Lane MD. A 30-kDa alternative translation product of the CCAAT/enhancer binding protein α message: transcriptional activator lacking antimitotic activity. Proc Natl Acad Sci USA. 1993;90:9606–10.
30. Müller C, Bremer A, Schreiber S, Eichwald S, Calkhoven CF. Nucleolar retention of a translational C/EBPα isoform stimulates rDNA transcription and cell size. EMBO J. 2010;29:897–909.
31. Lincoln AJ, Monczak Y, Williams SC, Johnson PF. Inhibition of CCAAT/enhancer-binding protein α and β translation by upstream open reading frames. J Biol Chem. 1998;273:9552–60.
32. Calkhoven CF, Müller C, Leutz A. Translational control of C/EBPα and C/EBPβ isoform expression. Genes Dev. 2000;14:1920–32.
33. Timchenko LT, Iakova P, Welm AL, Cai ZJ, Timchenko NA. Calreticulin interacts with C/EBPα and C/EBPβ mRNAs and represses translation of C/EBP proteins. Mol Cell Biol. 2002;22:7242–57.
34. Ross SE, Radomska HS, Wu B, Zhang P, Winnay JN, Bajnok L, et al. Phosphorylation of C/EBPα inhibits granulopoiesis. Mol Cell Biol. 2004;24:675–86.
35. Ross SE, Erickson RL, Hemati N, MacDougald OA. Glycogen synthase kinase 3 is an insulin-regulated C/EBPα kinase. Mol Cell Biol. 1999;19:8433–41.
36. Behre G, Singh SM, Liu H, Bortolin LT, Christopeit M, Radomska HS, et al. Ras signaling enhances the activity of C/EBPα to induce granulocytic differentiation by phosphorylation of serine 248. J Biol Chem. 2002;277:26293–9.
37. Mahoney CW, Shuman J, McKnight SL, Chen HC, Huang KP. Phosphorylation of CCAAT-enhancer binding protein by protein kinase C attenuates site-selective DNA binding. J Biol Chem. 1992;267:19396–403.
38. Kim J, Cantwell CA, Johnson PF, Pfarr CM, Williams SC. Transcriptional activity of CCAAT/enhancer-binding proteins is controlled by a conserved inhibitory domain that is a target for sumoylation. J Biol Chem. 2002;277:38037–44.
39. Subramanian L, Benson MD, Iñiguez-Lluhí JA. A synergy control motif within the attenuator domain of CCAAT/enhancer-binding protein α inhibits transcriptional synergy through its PIASy-enhanced modification by SUMO-1 or SUMO-3. J Biol Chem. 2003;278:9134–41.
40. Hankey W, Silver M, Sun BS, Zibello T, Berliner N, Khanna-Gupta A. Differential effects of sumoylation on the activities of CCAAT enhancer binding protein α (C/EBPα) p42 versus p30 may contribute in part, to aberrant C/EBPα activity in acute leukemias. Hematol Rep. 2011;3:e5.
41. Ren J, Li D, Li Y, Lan X, Zheng J, Wang X, et al. HDAC3 interacts with sumoylated C/EBPα to negatively regulate the LXRα expression in rat hepatocytes. Mol Cell Endocrinol. 2013;374:35–45.
42. Hegde VL, Tomar S, Jackson A, Rao R, Yang X, Singh UP, et al. Distinct microRNA expression profile and targeted biological pathways in functional myeloid-derived suppressor cells induced by Δ9-tetrahydrocannabinol in vivo: regulation of CCAAT/enhancer-binding protein α by microRNA-690. J Biol Chem. 2013;288:36810–26.
43. Keeshan K, He Y, Wouters BJ, Shestova O, Xu L, Sai H, et al. Tribbles homolog 2 inactivates C/EBPα and causes acute myelogenous leukemia. Cancer Cell. 2006;10:401–11.
44. Keeshan K, Bailis W, Dedhia PH, Vega ME, Shestova O, Xu L, et al. Transformation by Tribbles homolog 2 (Trib2) requires both the Trib2 kinase domain and COP1 binding. Blood. 2010;116:4948–57.
45. Yoshida A, Kato JY, Nakamae I, Yoneda-Kato N. COP1 targets C/EBPα for degradation and induces acute myeloid leukemia via Trib1. Blood. 2013;122:1750–60.
46. Umek RM, Friedman AD, McKnight SL. CCAAT-enhancer binding protein: a component of a differentiation switch. Science. 1991;251:288–92.
47. Timchenko NA, Wilde M, Nakanishi M, Smith JR, Darlington GJ. CCAAT/enhancer-binding protein α (C/EBP α) inhibits cell proliferation through the p21 (WAF-1/CIP-1/SDI-1) protein. Genes Dev. 1996;10:804–15.
48. Wang H, Iakova P, Wilde M, Welm A, Goode T, Roesler WJ, et al. C/EBPα arrests cell proliferation through direct inhibition of Cdk2 and Cdk4. Mol Cell. 2001;8:817–28.
49. Wang QF, Cleaves R, Kummalue T, Nerlov C, Friedman AD. Cell cycle inhibition mediated by the outer surface of the C/EBPα basic region is required but not sufficient for granulopoiesis. Oncogene. 2003;22:2548–57.
50. Wang GL, Iakova P, Wilde M, Awad S, Timchenko NA. Liver tumors escape negative control of proliferation via PI3 K/Akt-mediated block of C/EBPα growth inhibitory activity. Genes Dev. 2004;18:912–25.
51. Porse BT, Pedersen TA, Hasemann MS, Schuster MB, Kirstetter P, Luedde T, et al. The proline-histidine-rich CDK2/CDK4 interaction region of C/EBPα is dispensable for C/EBPα-mediated growth regulation in vivo. Mol Cell Biol. 2006;26:1028–37.
52. Pulikkan JA, Peramangalam PS, Dengler V, Ho PA, Preudhomme C, Meshinchi S, et al. C/EBPα regulated microRNA-34a targets E2F3 during granulopoiesis and is down-regulated in AML with CEBPA mutations. Blood. 2010;116:5638–49.
53. Dooher JE, Paz-Priel I, Houng S, Baldwin AS Jr, Friedman AD. C/EBPα, C/EBPα oncoproteins, or C/EBPβ preferentially bind NF-κB p50 compared with p65, focusing therapeutic targeting on the C/EBP:p50 interaction. Mol Cancer Res. 2011;9:1395–405.
54. Ye M, Zhang H, Amabile G, Yang H, Staber PB, Zhang P, et al. C/EBPα controls acquisition and maintenance of adult haematopoietic stem cell quiescence. Nat Cell Biol. 2013;15:385–94.
55. Hasemann MS, Lauridsen FK, Waage J, Jakobsen JS, Frank AK, Schuster MB, et al. C/EBPα 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.
56. Birkenmeier EH, Gwynn B, Howard S, Jerry J, Gordon JI, Landschulz WH, et al. Tissue-specific expression, developmental regulation, and genetic mapping of the gene encoding CCAAT/enhancer binding protein. Genes Dev. 1989;3:1146–56.
57. Flodby P, Barlow C, Kylefjord H, Ahrlund-Richter L, Xanthopoulos KG. Increased hepatic cell proliferation and lung abnormalities in mice deficient in CCAAT/enhancer binding protein α. J Biol Chem. 1996;271:24753–60.
58. Scott LM, Civin CI, Rorth P, Friedman AD. A novel temporal expression pattern of three C/EBP family members in differentiating myelomonocytic cells. Blood. 1992;80:1725–35.
59. Iwasaki H, Mizuno S, Arinobu Y, Ozawa H, Mori Y, Shigematsu H, et al. The order of expression of transcription factors directs hierarchical specification of hematopoietic lineages. Genes Dev. 2006;20:3010–21.
60. 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/EBPα. Immunity. 2004;21:853–63.
61. Wang ND, Finegold MJ, Bradley A, Ou CN, Abdelsayed SV, Wilde MD, Taylor LR, Wilson DR, Darlington GJ. Impaired energy homeostasis in C/EBPα knockout mice. Science. 1995;269:1108–12.
62. 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 α-deficient mice. Proc Natl Acad Sci USA. 1997;94:569–74.
63. Heath V, Suh HC, Holman M, Renn K, Gooya JM, Parkin S, et al. C/EBPα deficiency results in hyperproliferation of hematopoietic progenitor cells and disrupts macrophage development in vitro and in vivo. Blood. 2004;104:1639–47.
64. Ma O, Hong S, Guo H, Ghiaur G, Friedman AD. Granulopoiesis requires increased C/EBPα compared to monopoiesis, correlated with elevated Cebpa in immature G-CSF receptor versus M-CSF receptor expressing cells. PLoS One. 2014;9:e95784.
65. 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;38:576–89.
66. Wang D, D’Costa J, Civin CI, Friedman AD. C/EBPα directs monocytic commitment of primary myeloid progenitors. Blood. 2006;108:1223–9.
67. Fukuchi Y, Shibata F, Ito M, Goto-Koshino Y, Sotomaru Y, Ito M, et al. Comprehensive analysis of myeloid lineage conversion using mice expressing an inducible form of C/EBPα. EMBO J. 2006;25:3398–410.
68. Suh HC, Gooya J, Renn K, Friedman AD, Johnson PF, Keller JR. C/EBPα determines hematopoietic cell fate in multipotential progenitor cells by inhibiting erythroid differentiation and inducing myeloid differentiation. Blood. 2006;107:4308–16.
69. Wang X, Scott E, Sawyers CL, Friedman AD. C/EBPα bypasses granulocyte colony-stimulating factor signals to rapidly induce PU.1 gene expression, stimulate granulocytic differentiation, and limit proliferation in 32D cl3 myeloblasts. Blood. 1999;94:560–71.
70. Cammenga J, Mulloy JC, Berguido FJ, MacGrogan D, Viale A, Nimer SD. Induction of C/EBPα activity alters gene expression and differentiation of human CD34+ cells. Blood. 2003;101:2206–14.
71. Lidonnici MR, Audia A, Soliera AR, Prisco M, Ferrari-Amorotti G, Waldron T, et al. Expression of the transcriptional repressor Gfi-1 is regulated by C/ΕΒPα and is involved in its proliferation and colony formation-inhibitory effects in p210BCR/ABL-expressing cells. Cancer Res. 2010;70:7949–59.
72. Federzoni EA, Humbert M, Torbett BE, Behre G, Fey MF, Tschan MP. CEBPA-dependent HK3 and KLF5 expression in primary AML and during AML differentiation. Sci Rep. 2014;4:4261.
73. Lekstrom-Himes JA, Dorman SE, Kopar P, Holland SM, Gallin JI. Neutrophil-specific granule deficiency results from a novel mutation with loss of function of the transcription factor CCAAT/enhancer binding protein ε. J Exp Med. 1999;189:1847–52.
74. Karsunky H, Zeng H, Schmidt T, Zevnik B, Kluge R, Schmid KW, et al. Inflammatory reactions and severe neutropenia in mice lacking the transcriptional repressor Gfi1. Nat Genet. 2002;30:295–300.
75. 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;18:109–20.
76. Diakiw SM, Kok CH, To LB, Lewis ID, Brown AL, D’Andrea RJ. The granulocyte-associated transcription factor Krüppel-like factor 5 is silenced by hypermethylation in acute myeloid leukemia. Leuk Res. 2012;36:110–6.
77. Fazi F, Rosa A, Fatica A, Gelmetti V, De Marchis ML, Nervi C, et al. A minicircuitry comprised of microRNA-223 and transcription factors NFI-A and C/EBPα regulates human granulopoiesis. Cell. 2005;123:819–31.
78. Katzerke C, Madan V, Gerloff D, Bräuer-Hartmann D, Hartmann JU, Wurm AA, et al. Transcription factor C/EBPα-induced microRNA-30c inactivates Notch1 during granulopoiesis and is downregulated in acute myeloid leukemia. Blood. 2013;122:2433–42.
79. Friedman AD. Transcriptional regulation of granulocyte and monocyte development. Oncogene. 2002;21:3377–90.
80. Friedman AD. Transcriptional control of granulocyte and monocyte development. Oncogene. 2007;26:6816–28.
81. Christy RJ, Kaestner KH, Geiman DE, Lane MD. CCAAT/enhancer binding protein gene promoter: binding of nuclear factors during differentiation of 3T3-L1 preadipocytes. Proc Natl Acad Sci USA. 1991;88:2593–7.
82. Guo H, Ma O, Speck NA, Friedman AD. Runx1 deletion or dominant inhibition reduces Cebpa transcription via conserved promoter and distal enhancer sites to favor monopoiesis over granulopoiesis. Blood. 2012;119:4408–18.
83. Wilson NK, Foster SD, Wang X, Knezevic K, Schütte J, Kaimakis P, et al. Combinatorial transcriptional control in blood stem/progenitor cells: genome-wide analysis of ten major transcriptional regulators. Cell Stem Cell. 2010;7:532–44.
84. Huang Y, Sitwala K, Bronstein J, Sanders D, Dandekar M, Collins C, et al. Identification and characterization of Hoxa9 binding sites in hematopoietic cells. Blood. 2012;119:388–98.
85. Collins C, Wang J, Miao H, Bronstein J, Nawer H, Xu T, et al. C/EBPα is an essential collaborator in Hoxa9/Meis1-mediated leukemogenesis. Proc Natl Acad Sci USA. 2014;111:9899–904.
86. 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;96:419–26.
87. Wölfler A, Danen-van Oorschot AA, Haanstra JR, Valkhof M, Bodner C, Vroegindeweij E, et al. Lineage-instructive function of C/EBPα in multipotent hematopoietic cells and early thymic progenitors. Blood. 2010;116:4116–25.
88. Skokowa J, Cario G, Uenalan M, Schambach A, Germeshausen M, Battmer K, et al. LEF-1 is crucial for neutrophil granulocytopoiesis and its expression is severely reduced in congenital neutropenia. Nat Med. 2006;12:1191–7.
89. Seifeddine R, Dreiem A, Blanc E, Fulchignoni-Lataud MC, Le Frère Belda MA, Lecuru F, et al. Hypoxia down-regulates CCAAT/enhancer binding protein-α expression in breast cancer cells. Cancer Res. 2008;68:2158–65.
90. Jiang Y, Xue ZH, Shen WZ, Du KM, Yan H, Yu Y, et al. Desferrioxamine induces leukemic cell differentiation potentially by hypoxia-inducible factor-1 α that augments transcriptional activity of CCAAT/enhancer-binding protein-α. Leukemia. 2005;19:1239–47.
91. Di Ruscio A, Ebralidze AK, Benoukraf T, Amabile G, Goff LA, Terragni J, et al. DNMT1-interacting RNAs block gene-specific DNA methylation. Nature. 2013;503:371–6.
92. Rieger MA, Hoppe PS, Smejkal BM, Eitelhuber AC, Schroeder T. Hematopoietic cytokines can instruct lineage choice. Science. 2009;325:217–8.
93. Jack GD, Zhang L, Friedman AD. M-CSF elevates c-Fos and phospho-C/EBPα(S21) via ERK whereas G-CSF stimulates SHP2 phosphorylation in marrow progenitors to contribute to myeloid lineage specification. Blood. 2009;114:2172–80.
94. Buchwalter G, Gross C, Wasylyk B. Ets ternary complex transcription factors. Gene. 2004;324:1–14.
95. Geest CR, Buitenhuis M, Laarhoven AG, Bierings MB, Bruin MC, Vellenga E, et al. p38 MAP kinase inhibits neutrophil development through phosphorylation of C/EBPα on serine 21. Stem Cells. 2009;27:2271–82.
96. Köffel R, Meshcheryakova A, Warszawska J, Hennig A, Wagner K, Jörgl A, et al. Monocytic cell differentiation from band-stage neutrophils under inflammatory conditions via MKK6 activation. Blood. 2014;124:2713–24.
97. Huang W, Horvath E, Eklund EA. PU.1, interferon regulatory factor (IRF) 2, and the interferon consensus sequence-binding protein (ICSBP/IRF8) cooperate to activate NF1 transcription in differentiating myeloid cells. J Biol Chem. 2007;282:6629–43.
98. Huang H, Woo AJ, Waldon Z, Schindler Y, Moran TB, Zhu HH, et al. A Src family kinase-Shp2 axis controls RUNX1 activity in megakaryocyte and T-lymphocyte differentiation. Genes Dev. 2012;26:1587–601.
99. Futami M, Zhu QS, Whichard ZL, Xia L, Ke Y, Neel BG, et al. G-CSF receptor activation of the Src kinase Lyn is mediated by Gab2 recruitment of the Shp2 phosphatase. Blood. 2011;118:1077–86.
100. Yuan H, Zhou J, Deng M, Zhang Y, Chen Y, Jin Y, et al. Sumoylation of CCAAT/enhancer-binding protein α promotes the biased primitive hematopoiesis of zebrafish. Blood. 2011;117:7014–20.
101. Scott EW, Simon MC, Anastasi J, Singh H. Requirement of transcription factor PU.1 in the development of multiple hematopoietic lineages. Science. 1994;265:1573–7.
102. Rosenbauer F, Wagner K, Kutok JL, Iwasaki H, Le Beau MM, Okuno Y, et al. Acute myeloid leukemia induced by graded reduction of a lineage-specific transcription factor, PU.1. Nat Genet. 2004;36:624–30.
103. Huang G, Zhang P, Hirai H, Elf S, Yan X, Chen Z, et al. PU.1 is a major downstream target of AML1 (RUNX1) in adult mouse hematopoiesis. Nat Genet. 2008;40:51–60.
104. Kummalue T, Friedman AD. Cross-talk between regulators of myeloid development: C/EBPα binds and activates the promoter of the PU.1 gene. J Leukoc Biol. 2003;74:464–70.
105. Yeamans C, Wang D, Paz-Priel I, Torbett BE, Tenen DG, Friedman AD. C/EBPα binds and activates the PU.1 distal enhancer to induce monocyte lineage commitment. Blood. 2007;110:3136–42.
106. Rangatia J, Vangala RK, Treiber N, Zhang P, Radomska H, Tenen DG, et al. Downregulation of c-Jun expression by transcription factor C/EBPα is critical for granulocytic lineage commitment. Mol Cell Biol. 2002;22:8681–94.
107. Reddy VA, Iwama A, Iotzova G, Schulz M, Elsasser A, Vangala RK, et al. Granulocyte inducer C/EBPα inactivates the myeloid master regulator PU.1: possible role in lineage commitment decisions. Blood. 2002;100:483–90.
108. Oelgeschläger M, Nuchprayoon I, Lüscher B, Friedman AD. C/EBP, c-Myb, and PU.1 cooperate to regulate the neutrophil elastase promoter. Mol Cell Biol. 1996;16:4717–25.
109. Kurotaki D, Yamamoto M, Nishiyama A, Uno K, Ban T, Ichino M, et al. IRF8 inhibits C/EBPα activity to restrain mononuclear phagocyte progenitors from differentiating into neutrophils. Nat Commun. 2014;5:4978.
110. Hsu CL, King-Fleischman AG, Lai AY, Matsumoto Y, Weissman IL, Kondo M. Antagonistic effect of CCAAT enhancer-binding protein-α and Pax5 in myeloid or lymphoid lineage choice in common lymphoid progenitors. Proc Natl Acad Sci USA. 2006;103:672–7.
111. Rekhtman N, Radparvar F, Evans T, Skoultchi AI. Direct interaction of hematopoietic transcription factors PU.1 and GATA-1: functional antagonism in erythroid cells. Genes Dev. 1999;13:1398–411.
112. Zhang P, Behre G, Pan J, Iwama A, Wara-Aswapati N, Radomska HS, et al. Negative cross-talk between hematopoietic regulators: GATA proteins repress PU.1. Proc Natl Acad Sci USA. 1999;96:8705–10.
113. Querfurth E, Schuster M, Kulessa H, Crispino JD, Döderlein G, Orkin SH, et al. Antagonism between C/EBPβ and FOG in eosinophil lineage commitment of multipotent hematopoietic progenitors. Genes Dev. 2000;14:2515–25.
114. Sharabi AB, Aldrich M, Sosic D, Olson EN, Friedman AD, Lee SH, et al. Twist-2 controls myeloid lineage development and function. PLoS Biol. 2008;6:e316.
115. Pabst T, Mueller BU, Zhang P, Radomska HS, Narravula S, Schnittger S, et al. Dominant-negative mutations of CEBPA, encoding CCAAT/enhancer binding protein-α (C/EBPα), in acute myeloid leukemia. Nat Genet. 2001;27:263–70.
116. 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 α in myelodysplastic syndromes and acute myeloid leukemias. Blood. 2002;99:1332–40.
117. Paz-Priel I, Friedman A. C/EBPα dysregulation in AML and ALL. Crit Rev Oncog. 2011;16:93–102.
118. Fuchs O, Provaznikova D, Kocova M, Kostecka A, Cvekova P, Neuwirtova R, et al. CEBPA polymorphisms and mutations in patients with acute myeloid leukemia, myelodysplastic syndrome, multiple myeloma and non-Hodgkin’s lymphoma. Blood Cells Mol Dis. 2008;40:401–5.
119. Kato N, Kitaura J, Doki N, Komeno Y, Watanabe-Okochi N, Togami K, et al. Two types of C/EBPα mutations play distinct but collaborative roles in leukemogenesis: lessons from clinical data and BMT models. Blood. 2011;117:221–33.
120. Kirstetter P, Schuster MB, Bereshchenko O, Moore S, Dvinge H, Kurz E, et al. Modeling of C/EBPα mutant acute myeloid leukemia reveals a common expression signature of committed myeloid leukemia-initiating cells. Cancer Cell. 2008;13:299–310.
121. Schuster MB, Frank AK, Bagger FO, Rapin N, Vikesaa J, Porse BT. Lack of the p42 form of C/EBPα leads to spontaneous immortalization and lineage infidelity of committed myeloid progenitors. Exp Hematol. 2013;41:882–93.
122. Cleaves R, Wang QF, Friedman AD. C/EBPαp30, a myeloid leukemia oncoprotein, limits G-CSF receptor expression but not terminal granulopoiesis via site-selective inhibition of C/EBP DNA binding. Oncogene. 2004;23:716–25.
123. Wang C, Chen X, Wang Y, Gong J, Hu G. C/EBPα30 plays transcriptional regulatory roles distinct from C/EBPα42. Cell Res. 2007;17:374–83.
124. Geletu M, Balkhi MY, Peer Zada AA, Christopeit M, Pulikkan JA, Trivedi AK, et al. Target proteins of C/EBPαp30 in AML: C/EBPαp30 enhances sumoylation of C/EBPαp42 via up-regulation of Ubc9. Blood. 2007;110:3301–9.
125. Bereshchenko O, Mancini E, Moore S, Bilbao D, Månsson R, Luc S, et al. Hematopoietic stem cell expansion precedes the generation of committed myeloid leukemia-initiating cells in C/EBPα mutant AML. Cancer Cell. 2009;16:390–400.
126. Wagner K, Zhang P, Rosenbauer F, Drescher B, Kobayashi S, Radomska HS, et al. Absence of the transcription factor CCAAT enhancer binding protein α results in loss of myeloid identity in bcr/abl-induced malignancy. Proc Natl Acad Sci USA. 2006;103:6338–43.
127. Ohlsson E, Hasemann MS, Willer A, Lauridsen FK, Rapin N, Jendholm J, et al. Initiation of MLL-rearranged AML is dependent on C/EBPα. J Exp Med. 2013;211:5–13.
128. 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;26:1527–36.
129. m. Exp Hematol. 2014 (in press).
130. Watanabe-Okochi N, Yoshimi A, Sato T, Ikeda T, Kumano K, Taoka K, et al. The shortest isoform of C/EBPβ, liver inhibitory protein (LIP), collaborates with Evi1 to induce AML in a mouse BMT model. Blood. 2013;121:4142–55.
131. Friedman AD. Leukemogenesis by CBF oncoproteins. Leukemia. 1999;13:1932–42.
132. Pabst T, Mueller BU, Harakawa N, Schoch C, Haferlach T, Behre G, et al. AML1-ETO downregulates the granulocytic differentiation factor C/EBPα in t(8;21) myeloid leukemia. Nat Med. 2001;7:444–51.
133. Liu P, Tarlé SA, Hajra A, Claxton DF, Marlton P, Freedman M, et al. Fusion between transcription factor CBFβ/PEBP2β and a myosin heavy chain in acute myeloid leukemia. Science. 1993;261:1041–4.
134. Tang JL, Hou HA, Chen CY, Liu CY, Chou WC, Tseng MH, et al. AML1/RUNX1 mutations in 470 adult patients with de novo acute myeloid leukemia: prognostic implication and interaction with other gene alterations. Blood. 2009;114:5352–61.
135. Grossmann V, Kohlmann A, Zenger M, Schindela S, Eder C, Weissmann S, et al. A deep-sequencing study of chronic myeloid leukemia patients in blast crisis (BC-CML) detects mutations in 76.9 % of cases. Leukemia. 2011;25:557–60.
136. Vainchencker W, Delhoummeau F, Constantinescu SN, Bernard OA. New mutations and pathogenesis of myeloproliferative neoplasms. Blood. 2011;118:1723–35.
137. Harada H, Harada Y, Tanaka H, Kimura A, Inaba T. Implications of somatic mutations in the AML1 gene in radiation-associated and therapy-related myelodysplastic syndrome/acute myeloid leukemia. Blood. 2003;101:673–80.
138. Zhao LJ, Wang YY, Li G, Ma LY, Xiong SM, Weng XQ, et al. Functional features of RUNX1 mutants in acute transformation of chronic myeloid leukemia and their contribution to inducing murine full-blown leukemia. Blood. 2012;119:2873–82.
139. Cuenco GM, Ren R. Cooperation of BCR-ABL and AML1/MDS1/EVI1 in blocking myeloid differentiation and rapid induction of an acute myelogenous leukemia. Oncogene. 2001;20:8236–48.
140. Ptasinska A, Assi SA, Mannari D, James SR, Williamson D, Dunne J, et al. Depletion of RUNX1/ETO in t(8;21) AML cells leads to genome-wide changes in chromatin structure and transcription factor binding. Leukemia. 2012;26:1829–41.
141. Network The Cancer Genome Atlas Research. Genomic and epigenomic landscapes of adult de novo acute myeloid leuekemia. New Engl J Med. 2013;368:2059–74.
142. Döhner K, Tobis K, Bischof T, Hein S, Schlenk RF, Fröhling S, et al. Mutation analysis of the transcription factor PU.1 in younger adults (16–60 years) with acute myeloid leukemia: a study of the AML Study Group Ulm (AMLSG ULM). Blood. 2013;102:3850.
143. Musialik E, Bujko M, Kober P, Grygorowicz MA, Libura M, Przestrzelska M, et al. Comparison of promoter DNA methylation and expression levels of genes encoding CCAAT/enhancer binding proteins in AML patients. Leuk Res. 2014;38:850–6.
144. Wouters BJ, Jordà 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;110:3706–14.
145. Alberich-Jordà M, Wouters B, Balastik M, Shapiro-Koss C, Zhang H, Di Ruscio A, et al. C/EBPγ deregulation results in differentiation arrest in acute myeloid leukemia. J Clin Invest. 2012;122:4490–504.
146. Zhang H, Alberich-Jorda M, Amabile G, Yang H, Staber PB, Di Ruscio A, et al. Sox4 is a key oncogenic target in C/EBPα mutant acute myeloid leukemia. Cancer Cell. 2013;24:575–88.
147. 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/EBPα and induce acute myelogenous leukemia. Blood. 2010;116:1321–8.
148. Liang KL, Rishi L, Keeshan K. Tribbles in acute leukemia. Blood. 2013;121:4265–70.
149. Radomska HS, Bassères DS, Zheng R, Zhang P, Dayaram T, Yamamoto Y, et al. Block of C/EBPα function by phosphorylation in acute myeloid leukemia with FLT3 activating mutations. J Exp Med. 2006;203:371–81.
150. Radomska HS, Alberich-Jordà M, Will B, Gonzalez D, Delwel R, Tenen DG. Targeting CDK1 promotes FLT3-activated acute myeloid leukemia differentiation through C/EBPα. J Clin Invest. 2012;122:2955–66.
151. Perrotti D, Calabretta B. Post-transcriptional mechanisms in BCR/ABL leukemogenesis: role of shuttling RNA-binding proteins. Oncogene. 2002;21:8577–83.
152. Hirai H, Zhang P, Dayaram T, Hetherington CJ, Mizuno S, Imanishi J, et al. C/EBPβ is required for ‘emergency’ granulopoiesis. Nat Immunol. 2006;7:732–9.
153. Jones LC, Lin ML, Chen SS, Krug U, Hofmann WK, Lee S, et al. Expression of C/EBPβ from the C/ebpα gene locus is sufficient for normal hematopoiesis in vivo. Blood. 2002;99:2032–6.