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The Oncoprotein MLL–ENL disturbs hematopoietic lineage determination and transforms a biphenotypic lymphoid/myeloid cell

Oncogene volume 22, pages 1629–1637 (2003)Cite this article

Abstract

Mixed-lineage leukemia (MLL) fusion proteins are associated with a unique class of leukemia that is characterized by the simultaneous expression of lymphoid-specific as well as myeloid-specific genes. Here we report the first experimental model of MLL. Murine bone marrow cells were retrovirally transduced to express the MLL–eleven nineteen leukemia (MLL–ENL) fusion protein. When cultivated in flt-3 ligand, stem cell factor and interleukin-7 (IL-7) in a stroma-free culture system MLL–ENL-transduced as well as control cells showed a wave of B-lymphopoiesis. Whereas the controls exhausted their proliferative capacity in a CD19+/B220+ state, a continuously proliferating CD19−/B220+ cell population emerged in the MLL–ENL-transduced cultures. Despite the lymphoid surface marker, these cells were of monocytoid morphology. The immortalized cells contained unrearranged retrovirus, expressed MLL-ENL mRNA and were able to grow in syngenic recipients. From the diseased animals an MLL-ENL positive, B220+/CD19- cell type could be reisolated and cultivated in vitro. In analogy to human MLL, MLL–ENL-transformed cells not only coexpressed lymphocyte-specific (rag1, rag2, pax5, Tdt) and monocyte–specific genes (lysozyme, c-fms), but also showed rearrangements of the genomic immunoglobulin locus. This model shows that MLL–ENL influences events of early lineage determination and it will enable the investigation of the underlying molecular processes.

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References

  • Armstrong SA, Staunton JE, Silverman LB, Pieters R, den Boer ML, Minden MD, Sallan SE, Lander ES, Golub TR and Korsmeyer SJ . (2002). Nat. Genet, 30, 41–47.

  • Ayton PM and Cleary ML . (2001). Oncogene, 20, 5695–5707.

  • Behm FG, Raimondi SC, Frestedt JL, Liu Q, Crist WM, Downing JR, Rivera GK, Kersey JH and Pui CH . (1996). Blood, 87, 2870–2877.

  • Butler LH, Slany R, Cui X, Cleary ML and Mason DY . (1997). Blood, 89, 3361–3370.

  • Corral J, Lavenir I, Impey H, Warren AJ, Forster A, Larson TA, Bell S, McKenzie AN, King G and Rabbitts TH . (1996). Cell, 85, 853–861.

  • Cumano A, Paige CJ, Iscove NN and Brady G . (1992). Nature, 356, 612–615.

  • Dannaeus K, Johannisson A, Nilsson K and Jonsson JI . (1999). Exp. Hematol., 27, 1646–1654.

  • Dimartino JF and Cleary ML . (1999). Br. J. Haematol., 106, 614–626.

  • DiMartino JF, Miller T, Ayton PM, Landewe T, Hess JL, Cleary ML and Shilatifard A . (2000). Blood, 96, 3887–3893.

  • Djabali M, Selleri L, Parry P, Bower M, Young BD and Evans GA . (1992). Nat. Genet., 2, 113–118.

  • Dobson CL, Warren AJ, Pannell R, Forster A, Lavenir L, Corral J, Smith AJ and Rabbitts TH . (1999). EMBO J., 18, 3564–3574.

  • Dobson CL, Warren AJ, Pannell R, Forster A and Rabbitts TH . (2000). EMBO J., 19, 843–851.

  • Eberhard D, Jimenez G, Heavey B and Busslinger M . (2000). EMBO J., 19, 2292–2303.

  • Gu Y, Nakamura T, Alder H, Prasad R, Canaani O, Cimino G, Croce CM and Canaani E . (1992). Cell, 71, 701–708.

  • Hanson RD, Hess JL, Yu BD, Ernst P, van Lohuizen M, Berns A, van der Lugt NM, Shashikant CS, Ruddle FH, Seto M and Korsmeyer SJ . (1999). Proc. Natl. Acad. Sci. USA, 96, 14 372–14 377.

  • Hess JL, Yu BD, Li B, Hanson R and Korsmeyer SJ . (1997). Blood, 90, 1799–1806.

  • Huret JL, Dessen P and Bernheim A . (2001). Leukemia, 15, 987–989.

  • Kelly LM, Liu Q, Kutok JL, Williams IR, Boulton CL and Gilliland DG . (2002). Blood, 99, 310–318.

  • Kottaridis PO, Gale RE, Frew ME, Harrison G, Langabeer SE, Belton AA, Walker H, Wheatley K, Bowen DT, Burnett AK, Goldstone AH and Linch DC . (2001). Blood, 98, 1752–1759.

  • Lavau C, Du C, Thirman M and Zeleznik Le N . (2000a). EMBO J., 19, 4655–4664.

  • Lavau C, Luo RT, Du C and Thirman MJ . (2000b). Proc. Natl. Acad. Sci. USA, 97, 10984–10989.

  • Lavau C, Szilvassy SJ, Slany R and Cleary ML . (1997). EMBO J., 16, 4226–4237.

  • Mahmoudi T and Verrijzer CP . (2001). Oncogene, 20, 3055–3066.

  • Martensson IL, Melchers F and Winkler TH . (1997). J. Exp. Med., 185, 653–661.

  • Montecino-Rodriguez E, Leathers H and Dorshkind K . (2001). Nat. Immunol., 2, 83–88.

  • Nutt SL, Eberhard D, Horcher M, Rolink AG and Busslinger M . (2001). Int. Rev. Immunol., 20, 65–82.

  • Nutt SL, Heavey B, Rolink AG and Busslinger M . (1999). Nature, 401, 556–562.

  • Nutt SL, Morrison AM, Dorfler P, Rolink A and Busslinger M . (1998). EMBO J., 17, 2319–2333.

  • Pui CH, Frankel LS, Carroll AJ, Raimondi SC, Shuster JJ, Head DR, Crist WM, Land VJ, Pullen DJ and Steuber CP . (1991). Blood, 77, 440–447.

  • Schreiner SA, Garcia-Cuellar MP, Fey GH and Slany RK . (1999). Leukemia, 13, 1525–1533.

  • Schreiner SA, Birke M, Garcia-Cuellar MP, Zilles O, Greil H and Slany RK . (2001). Cancer Res., 61, 6480–6486

  • Slany RK, Lavau C and Cleary ML . (1998). Mol. Cell. Biol., 18, 122–129.

  • Tkachuk DC, Kohler S and Cleary ML . (1992). Cell, 71, 691–700.

  • Yagi H, Deguchi K, Aono A, Tani Y, Kishimoto T and Komori T . (1998). Blood, 92, 108–117.

  • Yeoh E-J, Ross ME, Shurtleff SA, Williams WK, Patel D, Mahfouz R, Behm FG, Raimondi SC, Relling MV, Patel A, Cheng C, Campana D, Wilkins D, Zhou X, Li J, Liu H, Pui CH, Evans WE, Naeve C, Wong L and Downing JR . (2002). Cancer Cell, 1, 133–143.

  • Yu BD, Hanson RD, Hess JL, Horning SE and Korsmeyer SJ . (1998). Proc. Natl. Acad. Sci. USA, 95, 10 632–10 636.

  • Yu BD, Hess JL, Horning SE, Brown GA and Korsmeyer SJ . (1995). Nature, 378, 505–508.

  • Ziemin-van der Poel S, McCabe NR, Gill HJ, Espinosa R, Ill Patel Y, Harden A, Rubinelli P, Smith SD, LeBeau MM, Rowley JD and Dzaz MO (1991). Proc. Natl. Acad. Sci. USA, 88, 10735–10739.

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Acknowledgements

We are grateful to Gary Nolan for the gift of the Phoenix-E packaging cell line. We thank Renate Zimmermann for technical assistance and Georg Fey for continuous support. This work was supported by Grant SFB466/C7 and partially by Grants SFB473/B10 and SL27/4-1 from the DFG. RKS is a recipient of a Ria Freifrau-von-Fritsch Stiftung career development award.

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  1. Department of Genetics, University of Erlangen, Staudtstrasse 5, Erlangen, 91058, Germany

    B B Zeisig, M P García-Cuéllar, T H Winkler & R K Slany

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  1. B B Zeisig
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  2. M P García-Cuéllar
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  3. T H Winkler
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Correspondence to R K Slany.

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Zeisig, B., García-Cuéllar, M., Winkler, T. et al. The Oncoprotein MLL–ENL disturbs hematopoietic lineage determination and transforms a biphenotypic lymphoid/myeloid cell. Oncogene 22, 1629–1637 (2003). https://doi.org/10.1038/sj.onc.1206104

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