NKL homeobox gene activities in normal and malignant myeloid cells

Autoři: Stefan Nagel aff001;  Michaela Scherr aff002;  Roderick A. F. MacLeod aff001;  Claudia Pommerenke aff001;  Max Koeppel aff001;  Corinna Meyer aff001;  Maren Kaufmann aff001;  Iris Dallmann aff002;  Hans G. Drexler aff001
Působiště autorů: Department of Human and Animal Cell Lines, Leibniz-Institute DSMZ–German Collection of Microorganisms and Cell Cultures, Braunschweig, Germany aff001;  Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany aff002
Vyšlo v časopise: PLoS ONE 14(12)
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pone.0226212


Recently, we have documented a hematopoietic NKL-code mapping physiological expression patterns of NKL homeobox genes in early hematopoiesis and in lymphopoiesis, which spotlights genes deregulated in lymphoid malignancies. Here, we enlarge this map to include normal NKL homeobox gene expressions in myelopoiesis by analyzing public expression profiling data and primary samples from developing and mature myeloid cells. We thus uncovered differential activities of six NKL homeobox genes, namely DLX2, HHEX, HLX, HMX1, NKX3-1 and VENTX. We further examined public expression profiling data of 251 acute myeloid leukemia (AML) and 183 myelodysplastic syndrome (MDS) patients, thereby identifying 24 deregulated genes. These results revealed frequent deregulation of NKL homeobox genes in myeloid malignancies. For detailed analysis we focused on NKL homeobox gene NANOG, which acts as a stem cell factor and is correspondingly expressed alone in hematopoietic progenitor cells. We detected aberrant expression of NANOG in a small subset of AML patients and in AML cell line NOMO-1, which served as a model. Karyotyping and genomic profiling discounted rearrangements of the NANOG locus at 12p13. But gene expression analyses of AML patients and AML cell lines after knockdown and overexpression of NANOG revealed regulators and target genes. Accordingly, NKL homeobox genes HHEX, DLX5 and DLX6, stem cell factors STAT3 and TET2, and the NOTCH-pathway were located upstream of NANOG while NKL homeobox genes HLX and VENTX, transcription factors KLF4 and MYB, and anti-apoptosis-factor MIR17HG represented target genes. In conclusion, we have extended the NKL-code to the myeloid lineage and thus identified several NKL homeobox genes deregulated in AML and MDS. These data indicate a common oncogenic role of NKL homeobox genes in both lymphoid and myeloid malignancies. For misexpressed NANOG we identified an aberrant regulatory network, which contributes to the understanding of the oncogenic activity of NKL homeobox genes.

Klíčová slova:

Acute myeloid leukemia – Apoptosis – Bone marrow cells – Cell differentiation – Gene expression – Monocytes – Homeobox – HL60 cells


1. Weiskopf K, Schnorr PJ, Pang WW, Chao MP, Chhabra A, Seita J, et al. Myeloid cell origins, differentiation, and clinical implications. Microbiol Spectr. 2016;4(5). doi: 10.1128/microbiolspec.MCHD-0031-2016 27763252

2. Italiani P, Boraschi D. Development and functional differentiation of tissue-resident versus monocyte-derived macrophages in inflammatory reactions. Results Probl Cell Differ. 2017;62:23–43. doi: 10.1007/978-3-319-54090-0_2 28455704

3. Naik SH, Perié L, Swart E, Gerlach C, van Rooij N, de Boer RJ, et al. Diverse and heritable lineage imprinting of early haematopoietic progenitors. Nature. 2013;496(7444):229–232. doi: 10.1038/nature12013 23552896

4. Miyawaki K, Arinobu Y, Iwasaki H, Kohno K, Tsuzuki H, Iino T, et al. CD41 marks the initial myelo-erythroid lineage specification in adult mouse hematopoiesis: redefinition of murine common myeloid progenitor. Stem Cells. 2015;33(3):976–987. doi: 10.1002/stem.1906 25446279

5. Drissen R, Buza-Vidas N, Woll P, Thongjuea S, Gambardella A, Giustacchini A, et al. Distinct myeloid progenitor-differentiation pathways identified through single-cell RNA sequencing. Nat Immunol. 2016;17(6):666–676. doi: 10.1038/ni.3412 27043410

6. DiNardo CD, Cortes JE. Mutations in AML: prognostic and therapeutic implications. Hematology Am Soc Hematol Educ Program. 2016;2016(1):348–355. doi: 10.1182/asheducation-2016.1.348 27913501

7. Basilico S, Göttgens B. Dysregulation of haematopoietic stem cell regulatory programs in acute myeloid leukaemia. J Mol Med (Berl). 2017;95(7):719–727.

8. Abate-Shen C. Deregulated homeobox gene expression in cancer: cause or consequence? Nat Rev Cancer. 2002;2(10):777–785. doi: 10.1038/nrc907 12360280

9. Dunwell TL, Holland PW. Diversity of human and mouse homeobox gene expression in development and adult tissues. BMC Dev Biol. 2016;16(1):40. doi: 10.1186/s12861-016-0140-y 27809766

10. Hunt P, Gulisano M, Cook M, Sham MH, Faiella A, Wilkinson D, et al. A distinct Hox code for the branchial region of the vertebrate head. Nature. 1991;353(6347):861–864. doi: 10.1038/353861a0 1682814

11. Depew MJ, Simpson CA, Morasso M, Rubenstein JL. Reassessing the Dlx code: the genetic regulation of branchial arch skeletal pattern and development. J Anat. 2005;207(5):501–561. doi: 10.1111/j.1469-7580.2005.00487.x 16313391

12. Nagel S, Pommerenke C, Scherr M, Meyer C, Kaufmann M, Battmer K, et al. NKL homeobox gene activities in hematopoietic stem cells, T-cell development and T-cell leukemia. PLoS One. 2017;12(2):e0171164. doi: 10.1371/journal.pone.0171164 28151996

13. Nagel S, MacLeod RAF, Meyer C, Kaufmann M, Drexler HG. NKL homeobox gene activities in B-cell development and lymphomas. PLoS One. 2018;13(10):e0205537. doi: 10.1371/journal.pone.0205537 30308041

14. Nagel S, Pommerenke C, Meyer C, Kaufmann M, MacLeod RAF, Drexler HG. NKL homeobox gene MSX1 acts like a tumor suppressor in NK-cell leukemia. Oncotarget. 2017;8(40):66815–66832. doi: 10.18632/oncotarget.18609 28977998

15. Holland PW, Booth HA, Bruford EA. Classification and nomenclature of all human homeobox genes. BMC Biol. 2007;5:47. doi: 10.1186/1741-7007-5-47 17963489

16. Nagel S, Pommerenke C, MacLeod RAF, Meyer C, Kaufmann M, Fähnrich S, et al. Deregulated expression of NKL homeobox genes in T-cell lymphomas. Oncotarget. 2019;10(35):3227–3247. doi: 10.18632/oncotarget.26929 31143370

17. Villarese P, Lours C, Trinquand A, Le Noir S, Belhocine M, Lhermitte L, et al. TCRα rearrangements identify a subgroup of NKL-deregulated adult T-ALLs associated with favorable outcome. Leukemia. 2018;32(1):61–71. doi: 10.1038/leu.2017.176 28592888

18. Starkova J, Gadgil S, Qiu YH, Zhang N, Hermanova I, Kornblau SM, et al. Up-regulation of homeodomain genes, DLX1 and DLX2, by FLT3 signaling. Haematologica. 2011;96(6):820–828. doi: 10.3324/haematol.2010.031179 21357706

19. Kawahara M, Pandolfi A, Bartholdy B, Barreyro L, Will B, Roth M, et al. H2.0-like homeobox regulates early hematopoiesis and promotes acute myeloid leukemia. Cancer Cell. 2012;22(2):194–208. doi: 10.1016/j.ccr.2012.06.027 22897850

20. Rawat VP, Arseni N, Ahmed F, Mulaw MA, Thoene S, Heilmeier B, et al. The vent-like homeobox gene VENTX promotes human myeloid differentiation and is highly expressed in acute myeloid leukemia. Proc Natl Acad Sci U S A. 2010;107(39):16946–16951. doi: 10.1073/pnas.1001878107 20833819

21. Saunders A, Faiola F, Wang J. Concise review: pursuing self-renewal and pluripotency with the stem cell factor Nanog. Stem Cells. 2013;31(7):1227–1236. doi: 10.1002/stem.1384 23653415

22. 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(6):894–904. doi: 10.1182/blood-2013-02-485771 24363398

23. Merryweather-Clarke AT, Atzberger A, Soneji S, Gray N, Clark K, Waugh C, et al. Global gene expression analysis of human erythroid progenitors. Blood. 2011;117(13):e96–108. doi: 10.1182/blood-2010-07-290825 21270440

24. Klein HU, Ruckert C, Kohlmann A, Bullinger L, Thiede C, Haferlach T, et al. Quantitative comparison of microarray experiments with published leukemia related gene expression signatures. BMC Bioinformatics. 2009;10:422. doi: 10.1186/1471-2105-10-422 20003504

25. Pellagatti A, Cazzola M, Giagounidis A, Perry J, Malcovati L, Della Porta MG, et al. Deregulated gene expression pathways in myelodysplastic syndrome hematopoietic stem cells. Leukemia. 2010;24(4):756–764. doi: 10.1038/leu.2010.31 20220779

26. Huang da W, Sherman BT, Lempicki RA. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc. 2009;4(1):44–57. doi: 10.1038/nprot.2008.211 19131956

27. Quentmeier H, Pommerenke C, Dirks WG, Eberth S, Koeppel M, MacLeod RAF, et al. The LL-100 panel: 100 cell lines for blood cancer studies. Sci Rep. 2019;9(1):8218. doi: 10.1038/s41598-019-44491-x 31160637

28. Drexler HG. Guide to leukemia-lymphoma cell lines. 2nd edition, Braunschweig: DSMZ, 2010.

29. Venturini L, Battmer K, Castoldi M, Schultheis B, Hochhaus A, Muckenthaler MU, et al. Expression of the miR-17-92 polycistron in chronic myeloid leukemia (CML) CD34+ cells. Blood. 2007;109(10):4399–4405. doi: 10.1182/blood-2006-09-045104 17284533

30. Macleod RA, Kaufmann M, Drexler HG. Cytogenetic analysis of cancer cell lines. Methods Mol Biol. 2011;731:57–78. doi: 10.1007/978-1-61779-080-5_6 21516398

31. Ohnishi K, Tobita T, Sinjo K, Takeshita A, Ohno R. Modulation of homeobox B6 and B9 genes expression in human leukemia cell lines during myelomonocytic differentiation. Leuk Lymphoma. 1998;31(5–6):599–608. doi: 10.3109/10428199809057620 9922051

32. Hume DA, MacDonald KP. Therapeutic applications of macrophage colony-stimulating factor-1 (CSF-1) and antagonists of CSF-1 receptor (CSF-1R) signaling. Blood. 2012;119(8):1810–1820. doi: 10.1182/blood-2011-09-379214 22186992

33. Quentmeier H, Dirks WG, Macleod RA, Reinhardt J, Zaborski M, Drexler HG. Expression of HOX genes in acute leukemia cell lines with and without MLL translocations. Leuk Lymphoma. 2004;45(3):567–574. doi: 10.1080/10428190310001609942 15160920

34. Rao RC, Dou Y. Hijacked in cancer: the KMT2 (MLL) family of methyltransferases. Nat Rev Cancer. 2015;15(6):334–346. doi: 10.1038/nrc3929 25998713

35. Gaussmann A, Wenger T, Eberle I, Bursen A, Bracharz S, Herr I, et al. Combined effects of the two reciprocal t(4;11) fusion proteins MLL-AF4 and AF4-MLL confer resistance to apoptosis, cell cycling capacity and growth transformation. Oncogene 2007;26(23):3352–3363. doi: 10.1038/sj.onc.1210125 17130830

36. Justin N, Zhang Y, Tarricone C, Martin SR, Chen S, Underwood E, et al. Structural basis of oncogenic histone H3K27M inhibition of human polycomb repressive complex 2. Nat Commun. 2016;7:11316. doi: 10.1038/ncomms11316 27121947

37. Narboux-Neme N, Ekker M, Levi G, Heude E. Posterior axis formation requires Dlx5/Dlx6 expression at the neural plate border. PLoS One. 2019;14(3):e0214063. doi: 10.1371/journal.pone.0214063 30889190

38. Tohda S. NOTCH signaling roles in acute myeloid leukemia cell growth and interaction with other stemness-related signals. Anticancer Res. 2014;34(11):6259–6264. 25368222

39. Sato N, Meijer L, Skaltsounis L, Greengard P, Brivanlou AH. Maintenance of pluripotency in human and mouse embryonic stem cells through activation of Wnt signaling by a pharmacological GSK-3-specific inhibitor. Nat Med. 2004;10(1):55–63. doi: 10.1038/nm979 14702635

40. Tarafdar A, Dobbin E, Corrigan P, Freeburn R, Wheadon H. Canonical Wnt signaling promotes early hematopoietic progenitor formation and erythroid specification during embryonic stem cell differentiation. PLoS One. 2013;8(11):e81030. doi: 10.1371/journal.pone.0081030 24324557

41. Zhang P, Andrianakos R, Yang Y, Liu C, Lu W. Kruppel-like factor 4 (Klf4) prevents embryonic stem (ES) cell differentiation by regulating Nanog gene expression. J Biol Chem. 2010;285(12):9180–9189. doi: 10.1074/jbc.M109.077958 20071344

42. Do DV, Ueda J, Messerschmidt DM, Lorthongpanich C, Zhou Y, Feng B, et al. A genetic and developmental pathway from STAT3 to the OCT4-NANOG circuit is essential for maintenance of ICM lineages in vivo. Genes Dev. 2013;27(12):1378–1390. doi: 10.1101/gad.221176.113 23788624

43. Nagel S, Pommerenke C, Meyer C, Kaufmann M, MacLeod RAF, Drexler HG. Aberrant expression of NKL homeobox gene HLX in Hodgkin lymphoma. Oncotarget. 2018;9(18):14338–14353. doi: 10.18632/oncotarget.24512 29581848

44. Nagel S, Uphoff CC, Dirks WG, Pommerenke C, Meyer C, Drexler HG. Epstein-Barr virus (EBV) activates NKL homeobox gene HLX in DLBCL. PLoS One. 2019;14(5):e0216898. doi: 10.1371/journal.pone.0216898 31141539

45. Langlois T, da Costa Reis Monte-Mor B, Lenglet G, Droin N, Marty C, Le Couédic JP, et al. TET2 deficiency inhibits mesoderm and hematopoietic differentiation in human embryonic stem cells. Stem Cells. 2014;32(8):2084–2097. doi: 10.1002/stem.1718 24723429

46. Nagel S, Venturini L, Przybylski GK, Grabarczyk P, Schmidt CA, Meyer C, et al. Activation of miR-17-92 by NK-like homeodomain proteins suppresses apoptosis via reduction of E2F1 in T-cell acute lymphoblastic leukemia. Leuk Lymphoma. 2009;50(1):101–108. doi: 10.1080/10428190802626632 19148830

47. Weng H, Huang H, Dong B, Zhao P, Zhou H, Qu L. Inhibition of miR-17 and miR-20a by oridonin triggers apoptosis and reverses chemoresistance by derepressing BIM-S. Cancer Res. 2014;74(16):4409–4419. doi: 10.1158/0008-5472.CAN-13-1748 24872388

48. Garg N, Po A, Miele E, Campese AF, Begalli F, Silvano M, et al. microRNA-17-92 cluster is a direct Nanog target and controls neural stem cell through Trp53inp1. EMBO J. 2013;32(21):2819–2832. doi: 10.1038/emboj.2013.214 24076654

49. Shimozaki K, Nakajima K, Hirano T, Nagata S. Involvement of STAT3 in the granulocyte colony-stimulating factor-induced differentiation of myeloid cells. J Biol Chem. 1997;272(40):25184–25189. doi: 10.1074/jbc.272.40.25184 9312131

50. Caldenhoven E, Buitenhuis M, van Dijk TB, Raaijmakers JA, Lammers JW, Koenderman L, et al. Lineage-specific activation of STAT3 by interferon-gamma in human neutrophils. J Leukoc Biol. 1999;65(3):391–396. doi: 10.1002/jlb.65.3.391 10080544

51. Minami M, Inoue M, Wei S, Takeda K, Matsumoto M, Kishimoto T, et al. STAT3 activation is a critical step in gp130-mediated terminal differentiation and growth arrest of a myeloid cell line. Proc Natl Acad Sci U S A. 1996 Apr 30;93(9):3963–3966. doi: 10.1073/pnas.93.9.3963 8632998

52. Nakajima K, Yamanaka Y, Nakae K, Kojima H, Ichiba M, Kiuchi N, et al. A central role for Stat3 in IL-6-induced regulation of growth and differentiation in M1 leukemia cells. EMBO J. 1996;15(14):3651–3658. 8670868

53. Baek YS, Haas S, Hackstein H, Bein G, Hernandez-Santana M, Lehrach H, et al. Identification of novel transcriptional regulators involved in macrophage differentiation and activation in U937 cells. BMC Immunol. 2009;10:18. doi: 10.1186/1471-2172-10-18 19341462

54. Jankovic D, Gorello P, Liu T, Ehret S, La Starza R, Desjobert C, et al. Leukemogenic mechanisms and targets of a NUP98/HHEX fusion in acute myeloid leukemia. Blood. 2008;111(12):5672–5682. doi: 10.1182/blood-2007-09-108175 18388181

55. Jackson JT, Ng AP, Shields BJ, Haupt S, Haupt Y, McCormack MP. Hhex induces promyelocyte self-renewal and cooperates with growth factor independence to cause myeloid leukemia in mice. Blood Adv. 2018;2(4):347–360. doi: 10.1182/bloodadvances.2017013243 29453249

56. Nagel S, Ehrentraut S, Meyer C, Kaufmann M, Drexler HG, MacLeod RA. Oncogenic deregulation of NKL homeobox gene MSX1 in mantle cell lymphoma. Leuk Lymphoma. 2014;55(8):1893–1903. doi: 10.3109/10428194.2013.864762 24237447

57. Voeltzel T, Flores-Violante M, Zylbersztejn F, Lefort S, Billandon M, Jeanpierre S, et al. A new signaling cascade linking BMP4, BMPR1A, ΔNp73 and NANOG impacts on stem-like human cell properties and patient outcome. Cell Death Dis. 2018;9(10):1011. doi: 10.1038/s41419-018-1042-7 30262802

58. Gentner E, Vegi NM, Mulaw MA, Mandal T, Bamezai S, Claus R, et al. VENTX induces expansion of primitive erythroid cells and contributes to the development of acute myeloid leukemia in mice. Oncotarget. 2016;7(52):86889–86901. doi: 10.18632/oncotarget.13563 27888632

59. Beverdam A, Merlo GR, Paleari L, Mantero S, Genova F, Barbieri O, et al. Jaw transformation with gain of symmetry after Dlx5/Dlx6 inactivation: mirror of the past? Genesis. 2002;34(4):221–227. doi: 10.1002/gene.10156 12434331

60. Horie R, Hazbun A, Chen K, Cao C, Levine M, Horie T. Shared evolutionary origin of vertebrate neural crest and cranial placodes. Nature. 2018;560(7717):228–232. doi: 10.1038/s41586-018-0385-7 30069052

61. Zhang Z, Shi Y, Zhao S, Li J, Li C, Mao B. Xenopus Nkx6.3 is a neural plate border specifier required for neural crest development. PLoS One. 2014 Dec 22;9(12):e115165. doi: 10.1371/journal.pone.0115165 25531524

62. Hatano M, Roberts CW, Minden M, Crist WM, Korsmeyer SJ. Deregulation of a homeobox gene, HOX11, by the t(10;14) in T cell leukemia. Science. 1991;253(5015):79–82. doi: 10.1126/science.1676542 1676542

63. Ferrando AA, Neuberg DS, Staunton J, Loh ML, Huard C, Raimondi SC, et al. Gene expression signatures define novel oncogenic pathways in T cell acute lymphoblastic leukemia. Cancer Cell. 2002;1(1):75–87. doi: 10.1016/s1535-6108(02)00018-1 12086890

64. Dadi S, Le Noir S, Payet-Bornet D, Lhermitte L, Zacarias-Cabeza J, et al. TLX homeodomain oncogenes mediate T cell maturation arrest in T-ALL via interaction with ETS1 and suppression of TCRα gene expression. Cancer Cell. 2012;21(4):563–576. doi: 10.1016/j.ccr.2012.02.013 22516263

65. Kanei-Ishii C, Nomura T, Egoh A, Ishii S. Fbxw5 suppresses nuclear c-Myb activity via DDB1-Cul4-Rbx1 ligase-mediated sumoylation. Biochem Biophys Res Commun. 2012;426(1):59–64. doi: 10.1016/j.bbrc.2012.08.032 22910413

66. Zhang W, Sui Y, Ni J, Yang T. Insights into the Nanog gene: A propeller for stemness in primitive stem cells. Int J Biol Sci. 2016;12(11):1372–1381. doi: 10.7150/ijbs.16349 27877089

67. de Wit E, Bouwman BA, Zhu Y, Klous P, Splinter E, Verstegen MJ, et al. The pluripotent genome in three dimensions is shaped around pluripotency factors. Nature. 2013;501(7466):227–231. doi: 10.1038/nature12420 23883933

68. Denholtz M, Bonora G, Chronis C, Splinter E, de Laat W, Ernst J, et al. Long-range chromatin contacts in embryonic stem cells reveal a role for pluripotency factors and polycomb proteins in genome organization. Cell Stem Cell. 2013;13(5):602–616. doi: 10.1016/j.stem.2013.08.013 24035354

69. Assi SA, Imperato MR, Coleman DJL, Pickin A, Potluri S, Ptasinska A, et al. Subtype-specific regulatory network rewiring in acute myeloid leukemia. Nat Genet. 2019;51(1):151–162. doi: 10.1038/s41588-018-0270-1 30420649

70. Vliet-Gregg PA, Hamilton JR, Katzenellenbogen RA. Human papillomavirus 16E6 and NFX1-123 potentiate Notch signaling and differentiation without activating cellular arrest. Virology. 2015;478:50–60. doi: 10.1016/j.virol.2015.02.002 25723053

71. Tsunematsu R, Nakayama K, Oike Y, Nishiyama M, Ishida N, Hatakeyama S, et al. Mouse Fbw7/Sel-10/Cdc4 is required for notch degradation during vascular development. J Biol Chem. 2004;279(10):9417–9423. doi: 10.1074/jbc.M312337200 14672936

72. Wu L, Sun T, Kobayashi K, Gao P, Griffin JD. Identification of a family of mastermind-like transcriptional coactivators for mammalian notch receptors. Mol Cell Biol. 2002;22(21):7688–7700. doi: 10.1128/MCB.22.21.7688-7700.2002 12370315

73. Tan Y, Sementino E, Xu J, Pei J, Liu Z, Ito TK, et al. The homeoprotein Dlx5 drives murine T-cell lymphomagenesis by directly transactivating Notch and upregulating Akt signaling. Oncotarget. 2017;8(9):14941–14956. doi: 10.18632/oncotarget.14784 28122332

74. Wang XF, Zhang BH, Lu XQ, Wang RQ. DLX5 gene regulates the Notch signaling pathway to promote glomerulosclerosis and interstitial fibrosis in uremic rats. J Cell Physiol. 2019, in press.

75. Dal Bo M, Bomben R, Hernández L, Gattei V. The MYC/miR-17-92 axis in lymphoproliferative disorders: A common pathway with therapeutic potential. Oncotarget. 2015;6(23):19381–19392. doi: 10.18632/oncotarget.4574 26305986

76. Maher CA, Palanisamy N, Brenner JC, Cao X, Kalyana-Sundaram S, Luo S, et al. Chimeric transcript discovery by paired-end transcriptome sequencing. Proc Natl Acad Sci U S A. 2009;106(30):12353–12358. doi: 10.1073/pnas.0904720106 19592507

77. Zhou X, Smith AJ, Waterhouse A, Blin G, Malaguti M, Lin CY, et al. Hes1 desynchronizes differentiation of pluripotent cells by modulating STAT3 activity. Stem Cells. 2013;31(8):1511–1522. doi: 10.1002/stem.1426 23649667

78. Farthing CR, Ficz G, Ng RK, Chan CF, Andrews S, Dean W, et al. Global mapping of DNA methylation in mouse promoters reveals epigenetic reprogramming of pluripotency genes. PLoS Genet. 2008;4(6):e1000116. doi: 10.1371/journal.pgen.1000116 18584034

79. Al-Khtib M, Blachère T, Guérin JF, Lefèvre A. Methylation profile of the promoters of Nanog and Oct4 in ICSI human embryos. Hum Reprod. 2012;27(10):2948–2954. doi: 10.1093/humrep/des284 22914767

80. Tsuji-Takayama K, Inoue T, Ijiri Y, Otani T, Motoda R, Nakamura S, et al. Demethylating agent, 5-azacytidine, reverses differentiation of embryonic stem cells. Biochem Biophys Res Commun. 2004;323(1):86–90. doi: 10.1016/j.bbrc.2004.08.052 15351705

81. Doege CA, Inoue K, Yamashita T, Rhee DB, Travis S, Fujita R, et al. Early-stage epigenetic modification during somatic cell reprogramming by Parp1 and Tet2. Nature. 2012;488(7413):652–655. doi: 10.1038/nature11333 22902501

82. Rasmussen KD, Berest I, Keβler S, Nishimura K, Simón-Carrasco L, Vassiliou GS, et al. TET2 binding to enhancers facilitates transcription factor recruitment in hematopoietic cells. Genome Res. 2019;29(4):564–575. doi: 10.1101/gr.239277.118 30796038

83. Bowman RL, Levine RL. TET2 in normal and malignant hematopoiesis. Cold Spring Harb Perspect Med. 2017;7(8). pii: a026518. doi: 10.1101/cshperspect.a026518 28242787

84. Wang Y, Xiao M, Chen X, Chen L, Xu Y, Lv L, et al. WT1 recruits TET2 to regulate its target gene expression and suppress leukemia cell proliferation. Mol Cell. 2015;57(4):662–673. doi: 10.1016/j.molcel.2014.12.023 25601757

85. Suprynowicz FA, Upadhyay G, Krawczyk E, Kramer SC, Hebert JD, Liu X, et al. Conditionally reprogrammed cells represent a stem-like state of adult epithelial cells. Proc Natl Acad Sci U S A. 2012;109(49):20035–20040. doi: 10.1073/pnas.1213241109 23169653

86. Yan H, Zhang DY, Li X, Yuan XQ, Yang YL, Zhu KW, et al. Long non-coding RNA GAS5 polymorphism predicts a poor prognosis of acute myeloid leukemia in Chinese patients via affecting hematopoietic reconstitution. Leuk Lymphoma. 2017;58(8):1948–1957. doi: 10.1080/10428194.2016.1266626 27951730

87. Dhaliwal NK, Abatti LE, Mitchell JA. KLF4 protein stability regulated by interaction with pluripotency transcription factors overrides transcriptional control. Genes Dev. 2019, in press.

88. Feinberg MW, Wara AK, Cao Z, Lebedeva MA, Rosenbauer F, Iwasaki H, et al. The Kruppel-like factor KLF4 is a critical regulator of monocyte differentiation. EMBO J. 2007;26(18):4138–4148. doi: 10.1038/sj.emboj.7601824 17762869

89. Morris VA, Cummings CL, Korb B, Boaglio S, Oehler VG. Deregulated KLF4 expression in myeloid leukemias alters cell proliferation and differentiation through microRNA and gene targets. Mol Cell Biol. 2015;36(4):559–573. doi: 10.1128/MCB.00712-15 26644403

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