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The anti-apoptotic gene BCL2A1 is a novel transcriptional target of PU.1

Leukemia volume 24, pages 1073–1076 (2010)Cite this article

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The transcription factor PU.1 is a key player in myeloid and B-cell development as evidenced by PU.1 knockout mouse models. PU.1 is necessary for the generation and function of macrophages and granulocytes through the regulation of essential myeloid genes such as the granulocyte/macrophage colony-stimulating factor receptor (GM-CSFR), the macrophage CSF (M-CSF), the granulocyte CSF (G-CSF), CD11b, myeloperoxidase, lysozyme, neutrophil elastase, CD45, and others.1, 2, 3

Anti-apoptotic Bcl2 proteins are frequently overexpressed during tumorigenesis4 and three of them are expressed in myeloid cells: BCL2A1 (also designated as A1 or BFL-1) and Mcl-1 in neutrophils, whereas BCL2A1 and Bcl-xL can both be upregulated in macrophages by proinflammatory stimuli in vitro. Sevilla et al.5 reported that PU.1 together with another Ets-family member, Ets2, transactivate the Bcl-xL promoter and increase macrophage survival. Hamasaki et al.6 have shown that BCL2A1 deficiency accelerates spontaneous neutrophil apoptosis. Furthermore, it was reported that PU.1 is a direct target of caspase-3, an apoptosis executor, upon treatment of leukemic cells with DNA-damaging agents.7 In line, it was found that PU.1 induces cell death in a subset of myeloma cell lines by direct activation of TRAIL.8 Thus, Ets-family members and PU.1 directly and indirectly regulate cell death pathways.

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References

  1. Anderson KL, Nelson SL, Perkin HB, Smith KA, Klemsz MJ, Torbett BE . PU.1 is a lineage-specific regulator of tyrosine phosphatase CD45. J Biol Chem 2001; 276: 7637–7642.

    Article  CAS  PubMed  Google Scholar 

  2. Rosenbauer F, Tenen DG . Transcription factors in myeloid development: balancing differentiation with transformation. Nat Rev Immunol 2007; 7: 105–117.

    Article  CAS  PubMed  Google Scholar 

  3. Tenen DG . Disruption of differentiation in human cancer: AML shows the way. Nat Rev Cancer 2003; 3: 89–101.

    Article  CAS  PubMed  Google Scholar 

  4. Youle RJ, Strasser A . The BCL-2 protein family: opposing activities that mediate cell death. Nat Rev Mol Cell Biol 2008; 9: 47–59.

    Article  CAS  PubMed  Google Scholar 

  5. Sevilla L, Zaldumbide A, Carlotti F, Dayem MA, Pognonec P, Boulukos KE . Bcl-XL expression correlates with primary macrophage differentiation, activation of functional competence, and survival and results from synergistic transcriptional activation by Ets2 and PU.1. J Biol Chem 2001; 276: 17800–17807.

    Article  CAS  PubMed  Google Scholar 

  6. Hamasaki A, Sendo F, Nakayama K, Ishida N, Negishi I, Hatakeyama S . Accelerated neutrophil apoptosis in mice lacking A1-a, a subtype of the bcl-2-related A1 gene. J Exp Med 1998; 188: 1985–1992.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Zhao M, Duan XF, Wen DH, Chen GQ . PU.1, a novel caspase-3 substrate, partially contributes to chemotherapeutic agents-induced apoptosis in leukemic cells. Biochem Biophys Res Commun 2009; 382: 508–513.

    Article  CAS  PubMed  Google Scholar 

  8. Ueno S, Tatetsu H, Hata H, Iino T, Niiro H, Akashi K et al. PU 1 induces apoptosis in myeloma cells through direct transactivation of TRAIL. Oncogene 2009; 28: 4116–4125.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Altucci L, Rossin A, Raffelsberger W, Reitmair A, Chomienne C, Gronemeyer H . Retinoic acid-induced apoptosis in leukemia cells is mediated by paracrine action of tumor-selective death ligand TRAIL. Nat Med 2001; 7: 680–686.

    Article  CAS  PubMed  Google Scholar 

  10. Okuno Y, Huang G, Rosenbauer F, Evans EK, Radomska HS, Iwasaki H et al. Potential autoregulation of transcription factor PU 1 by an upstream regulatory element. Mol Cell Biol 2005; 25: 2832–2845.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Zong WX, Edelstein LC, Chen C, Bash J, Gelinas C . The prosurvival Bcl-2 homolog Bfl-1/A1 is a direct transcriptional target of NF-kappaB that blocks TNFalpha-induced apoptosis. Genes Dev 1999; 13: 382–387.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Yin W, Raffelsberger W, Gronemeyer H . Retinoic acid determines life span of leukemic cells by inducing antagonistic apoptosis-regulatory programs. Int J Biochem Cell Biol 2005; 37: 1696–1708.

    Article  CAS  PubMed  Google Scholar 

  13. Mueller BU, Pabst T, Fos J, Petkovic V, Fey MF, Asou N et al. ATRA resolves the differentiation block in t(15;17) acute myeloid leukemia by restoring PU.1 expression. Blood 2006; 107: 3330–3338.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Lin EY, Orlofsky A, Berger MS, Prystowsky MB . Characterization of A1, a novel hemopoietic-specific early-response gene with sequence similarity to bcl-2. J Immunol 1993; 151: 1979–1988.

    CAS  PubMed  Google Scholar 

  15. Liu CY, Chuang PI, Chou CL, Lin SM, Chen HC, Chou P et al. Cytoprotective response of A1, a Bcl-2 homologue expressed in mature human neutrophils and promyelocytic HL-60 cells, to oxidant stress-induced cell death. J Biomed Sci 2004; 11: 214–227.

    Article  CAS  PubMed  Google Scholar 

  16. Sevilla L, Aperlo C, Dulic V, Chambard JC, Boutonnet C, Pasquier O et al. The Ets2 transcription factor inhibits apoptosis induced by colony-stimulating factor 1 deprivation of macrophages through a Bcl-xL-dependent mechanism. Mol Cell Biol 1999; 19: 2624–2634.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Xia L, Wurmbach E, Waxman S, Jing Y . Upregulation of Bfl-1/A1 in leukemia cells undergoing differentiation by all-trans retinoic acid treatment attenuates chemotherapeutic agent-induced apoptosis. Leukemia 2006; 20: 1009–1016.

    Article  CAS  PubMed  Google Scholar 

  18. Rimmele P, Kosmider O, Mayeux P, Moreau-Gachelin F, Guillouf C . Spi-1/PU.1 participates in erythroleukemogenesis by inhibiting apoptosis in cooperation with Epo signaling and by blocking erythroid differentiation. Blood 2007; 109: 3007–3014.

    CAS  PubMed  Google Scholar 

  19. Tschan MP, Reddy VA, Ress A, Arvidsson G, Fey MF, Torbett BE . PU 1 binding to the p53 family of tumor suppressors impairs their transcriptional activity. Oncogene 2008; 27: 3489–3493.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Deborah Shan, Judith Laedrach, and Gustav Arvidsson for expert technical support. This work was supported by grants from the Swiss National Science Foundation 3100A0-118276 (to MPT) and 3100A0-112385 (to MFF and AT), the Bern University Research Foundation (to MPT), the Werner and Hedy Berger-Janser Foundation of Cancer Research (to MFF and MPT), the NIH, HL091219 and DK54938, the Joyce Klein Stock Gift (to BET), the Marlies-Schwegler Foundation, the Ursula-Hecht-Foundation for Leukemia Research, and the Bernese Foundation of Cancer Research (to MFF).

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Authors and Affiliations

  1. Department of Clinical Research, Experimental Oncology/Hematology, University of Bern, Bern, Switzerland

    M Jenal, J Batliner, A Tobler, M F Fey & M P Tschan

  2. Cancer Stem Cell Program, Novartis Institute of Functional Genomics, San Diego, CA, USA

    V A Reddy

  3. MLL Munich Leukemia Laboratory, Munich, Germany

    T Haferlach

  4. Department of Hematology, Inselspital, Bern University Hospital, Bern, Switzerland

    A Tobler

  5. Department of Medical Oncology, Inselspital, Bern University Hospital, Bern, Switzerland

    M F Fey & M P Tschan

  6. Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA, USA

    B E Torbett

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  1. M Jenal
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Correspondence to M P Tschan.

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Authorship

MJ designed the project, performed experiments, collected and analyzed all data, manuscript writing; JB was involved in knockdown experiments and expression analysis; VAR performed microarray analysis; TH provided AML samples, expression analysis; AT, MFF, and BET performed project planning and design, reviewed manuscript; MPT was the principal investigator and takes primary responsibility for the paper.

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Jenal, M., Batliner, J., Reddy, V. et al. The anti-apoptotic gene BCL2A1 is a novel transcriptional target of PU.1. Leukemia 24, 1073–1076 (2010). https://doi.org/10.1038/leu.2010.26

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