Normal Hemopoiesis

Overexpression of a hematopoietic transcriptional regulator EDAG induces myelopoiesis and suppresses lymphopoiesis in transgenic mice

Article metrics


Erythroid differentiation-associated gene (EDAG) is a hematopoietic tissue-specific gene that is highly expressed in the earliest CD34+ lin bone marrow (BM) cells and involved in the proliferation and differentiation of hematopoietic cells. To investigate the role of EDAG in hematopoiesis, we established an EDAG transgenic mouse model driven by human CD11a promoter. The transgenic mice showed increased mortality with severe organ infiltration by neutrophils, and the homeostasis of hematopoiesis was broken. The myelopoiesis was enhanced with expansion of myeloid cells in BM, increased peripheral granulocytes and extramedullary myelopoiesis in spleen. In contrast to myeloid cells, the lymphoid commitment was severely impaired with the B lymphopoiesis blocked at the transition from pro/pre-B I to pre-B II stage in BM and T thymocytes development blocked at the most immature stage (DN I). Moreover, we showed that EDAG was a transcriptional regulator which had transactivation activity and regulated the expression of several key transcription factors such as PU.1 and Pax5 in transgenic hematopoietic stem cells. These data suggested that EDAG was a key transcriptional regulator in maintaining the homeostasis of hematopoietic lineage commitment.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5


  1. 1

    Yang LV, Nicholson RH, Kaplan J, Galy A, Li L . Hemogen is a novel nuclear factor specifically expressed in mouse hematopoietic development and its human homologue EDAG maps to chromosome 9q22, a region containing breakpoints of hematological neoplasms. Mech Dev 2001; 104: 105–111.

  2. 2

    Wurtz T, Kruger A, Christersson C, Lundmark C . A new protein expressed in bone marrow cells and osteoblasts with implication in osteoblast recruitment. Exp Cell Res 2001; 263: 236–242.

  3. 3

    Yang LV, Wan J, Ge Y, Fu Z, Kim SY, Fujiwara Y et al. The GATA site-dependent hemogen promoter is transcriptionally regulated by GATA1 in hematopoietic and leukemia cells. Leukemia 2006; 20: 417–425.

  4. 4

    Yang LV, Heng HH, Wan J, Southwood CM, Gow A, Li L . Alternative promoters and polyadenylation regulate tissue-specific expression of Hemogen isoforms during hematopoiesis and spermatogenesis. Dev Dyn 2003; 228: 606–616.

  5. 5

    Li CY, Zhan YQ, Xu CW, Xu WX, Wang SY, Lv J et al. EDAG regulates the proliferation and differentiation of hematopoietic cells and resists cell apoptosis through the activation of nuclear factor-kappaB. Cell Death Differ 2004; 11: 1299–1308.

  6. 6

    Lv J, Xu WX, Wang SY, Zhan YQ, Jiang Y, Cai WM et al. Isolation and characterization of EDAG-1, a novel gene related to regulation in hematopoietic system. Sheng Wu Hua Xue Yu Sheng Wu Wu Li Xue Bao (Shanghai) 2001; 33: 641–646.

  7. 7

    Zhou Y, Xu WX, Zhan YQ, Li CY, Xu CW, Zheng H et al. Expression of EDAG-1 gene in human leukemia and lymphoma cell lines. Ai Zheng 2004; 23: 1238–1243.

  8. 8

    An LL, Li G, Wu KF, Ma XT, Zheng GG, Qiu LG et al. High expression of EDAG and its significance in AML. Leukemia 2005; 19: 1499–1502.

  9. 9

    Kawamura H, Kawamura T, Kokai Y, Mori M, Matsuura A, Oya H et al. Expansion of extrathymic T cells as well as granulocytes in the liver and other organs of granulocyte-colony stimulating factor transgenic mice: why they lost the ability of hybrid resistance. J Immunol 1999; 162: 5957–5964.

  10. 10

    Kondo M, Weissman IL, Akashi K . Identification of clonogenic common lymphoid progenitors in mouse bone marrow. Cell 1997; 91: 661–672.

  11. 11

    Akashi K, Traver D, Miyamoto T, Weissman IL . A clonogenic common myeloid progenitor that gives rise to all myeloid lineages. Nature 2000; 404: 193–197.

  12. 12

    Chen H, Ray-Gallet D, Zhang P, Hetherington CJ, Gonzalez DA, Zhang DE et al. PU.1 (Spi-1) autoregulates its expression in myeloid cells. Oncogene 1995; 11: 1549–1560.

  13. 13

    Miller BA, Antognetti G, Springer TA . Identification of cell surface antigens present on murine hematopoietic stem cells. J Immunol 1985; 134: 3286–3290.

  14. 14

    Mack DL, Leibowitz DS, Cooper S, Ramsey H, Broxmeyer HE, Hromas R . Downregulation of the myeloid homeobox protein Hex is essential for normal T-cell development. Immunology 2002; 107: 444–451.

  15. 15

    Virts EL, Diago O, Raschke WC . A CD45 minigene restores regulated isoform expression and immune function in CD45-deficient mice: therapeutic implications for human CD45-null severe combined immunodeficiency. Blood 2003; 101: 849–855.

  16. 16

    Hutchings P, Rosen H, O’Reilly L, Simpson E, Gordon S, Cooke A . Transfer of diabetes in mice prevented by blockade of adhesion-promoting receptor on macrophages. Nature 1990; 348: 639–642.

  17. 17

    Rolink A, Grawunder U, Winkler TH, Karasuyama H, Melchers F . IL-2 receptor alpha chain (CD25, TAC) expression defines a crucial stage in pre-B cell development. Int Immunol 1994; 6: 1257–1264.

  18. 18

    Godfrey DI, Kennedy J, Suda T, Zlotnik A . A developmental pathway involving four phenotypically and functionally distinct subsets of CD3−CD4−CD8− triple-negative adult mouse thymocytes defined by CD44 and CD25 expression. J Immunol 1993; 150: 4244–4252.

  19. 19

    Georgopoulos K . Haematopoietic cell-fate decisions, chromatin regulation and ikaros. Nat Rev Immunol 2002; 2: 162–174.

  20. 20

    Lecuyer E, Hoang T . SCL: from the origin of hematopoiesis to stem cells and leukemia. Exp Hematol 2004; 32: 11–24.

  21. 21

    Herblot S, Aplan PD, Hoang T . SCL transgenic mice gradient of E2A activity in B-cell development. Mol Cell Biol 2002; 22: 886–900.

  22. 22

    Sauvageau G, Lansdorp PM, Eaves CJ, Hogge DE, Dragowska WH, Reid DS et al. Differential expression of homeobox genes in functionally distinct CD34+ subpopulations of human bone marrow cells. Proc Natl Acad Sci USA 1994; 91: 12223–12227.

  23. 23

    Thorsteinsdottir U, Mamo A, Kroon E, Jerome L, Bijl J, Lawrence HJ et al. Overexpression of the myeloid leukemia-associated Hoxa9 gene in bone marrow cells induces stem cell expansion. Blood 2002; 99: 121–129.

  24. 24

    Sauvageau G, Thorsteinsdottir U, Hough MR, Hugo P, Lawrence HJ, Largman C et al. Overexpression of HOXB3 in hematopoietic cells causes defective lymphoid development and progressive myeloproliferation. Immunity 1997; 6: 13–22.

  25. 25

    Thorsteinsdottir U, Sauvageau G, Hough MR, Dragowska W, Lansdorp PM, Lawrence HJ et al. Overexpression of HOXA10 in murine hematopoietic cells perturbs both myeloid and lymphoid differentiation and leads to acute myeloid leukemia. Mol Cell Biol 1997; 17: 495–505.

  26. 26

    Ness SA, Engel JD . Vintage reds and whites: combinatorial transcription factor utilization in hematopoietic differentiation. Curr Opin Genet Dev 1994; 4: 718–724.

  27. 27

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

  28. 28

    McIvor Z, Hein S, Fiegler H, Schroeder T, Stocking C, Just U et al. The transient expression of Pu.1 commits multipotent progenitors to a myeloid fate, while continued expression favours macrophage over granulocyte differentiation. Exp Hematol 2003; 31: 39–47.

  29. 29

    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.

  30. 30

    Karafiat V, Dvorakova M, Pajer P, Kralova J, Horejsi Z, Cermak V et al. The leucine zipper region of Myb oncoprotein regulates the commitment of hematopoietic progenitors. Blood 2001; 98: 3668–3676.

  31. 31

    Urbanek P, Wang ZQ, Fetka I, Wagner EF, Busslinger M . Complete block of early B cell differentiation and altered patterning of the posterior midbrain in mice lacking Pax5/BSAP. Cell 1994; 79: 901–912.

  32. 32

    Maitra S, Atchison M . BSAP can repress enhancer activity by targeting PU.1 function. Mol Cell Biol 2000; 20: 1911–1922.

  33. 33

    DeKoter RP, Walsh JC, Singh H . PU1 regulates both cytokine-dependent proliferation and differentiation of granulocyte/macrophage progenitors. EMBO J 1998; 17: 4456–4468.

  34. 34

    Zhang P, Zhang X, Iwama A, Yu C, Smith KA, Mueller BU et al. PU 1 inhibits GATA-1 function and erythroid differentiation by blocking GATA-1 DNA binding. Blood 2000; 96: 2641–2648.

  35. 35

    Lv J, Xu WX, Wang SY, Jiang Y, Li CY, Cai WM et al. Overexpression of EDAG in NIH3T3 cells leads to malignant transformation. Sheng Wu Hua Xue Yu Sheng Wu Wu Li Xue Bao (Shanghai) 2002; 34: 95–98.

  36. 36

    Grisolano JL, O’Neal J, Cain J, Tomasson MH . An activated receptor tyrosine kinase, TEL/PDGFbetaR, cooperates with AML1/ETO to induce acute myeloid leukemia in mice. Proc Natl Acad Sci USA 2003; 100: 9506–9511.

  37. 37

    Braun BS, Tuveson DA, Kong N, Le DT, Kogan SC, Rozmus J et al. Somatic activation of oncogenic Kras in hematopoietic cells initiates a rapidly fatal myeloproliferative disorder. Proc Natl Acad Sci USA 2004; 101: 597–602.

Download references


This work was partially supported by Chinese National Natural Science Foundation Projects (30321003), Chinese National Science Foundation Key Program Projects (30630035) and Chinese State Key Projects for Basic Research (2002CB513103). The authors have no conflicting financial interests.

Author information

Correspondence to X-M Yang.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Li, C., Zhan, Y., Li, W. et al. Overexpression of a hematopoietic transcriptional regulator EDAG induces myelopoiesis and suppresses lymphopoiesis in transgenic mice. Leukemia 21, 2277–2286 (2007) doi:10.1038/sj.leu.2404901

Download citation


  • EDAG
  • myelopoiesis
  • lymphopoiesis
  • hematopoiesis
  • transactivator
  • lineage commitment

Further reading