Abstract
The t(12;21) translocation, generating the TEL/AML1 fusion protein, is the most common genetic lesion in childhood cancer. Using a bone marrow transplantation model, we demonstrate that TEL/AML1 expression impinges on normal hematopoietic differentiation, leading to the in vivo accumulation and persistence of an early progenitor compartment with a Sca1+/Kithi/CD11b+ phenotype and an increased self-renewal capacity, as documented by replating assays in vitro. Differentiation of these cells is not blocked, but the frequency of mature blood cells arising from TEL/AML1-transduced progenitors is low. Impaired differentiation is prominently observed in the pro-B-cell compartment, resulting in an proportional increase in early progenitors in vivo, consistent with the t(12;21) ALL phenotype. Despite the accumulation of both multipotent and B-cell progenitors in vivo, no leukemia induction was observed during an observation period of over 1 year. These results are consistent with findings in twins with concordant ALL, showing that TEL/AML1 generates a preleukemic clone in utero that persists for several years in a clinically covert fashion. Furthermore, our studies showed that the pointed domain of TEL/AML1, which recruits transcriptional repressors and directs oligomerization with either TEL/AML1 or wild-type TEL, was essential for the observed differentiation impairment and could not be replaced with another oligomerization domain.
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Abbreviations
- ALL:
-
acute lymphoblastic leukemia
- AML:
-
acute myelogenous leukemia
- AML1:
-
protein encoded by RUNX1
- A/E:
-
AML1/ETO
- CBF:
-
core-binding factor
- eGFP:
-
enhanced gree fluorescent protein
- IL3:
-
interleukin-3
- IL7:
-
interleukin-7
- PTD:
-
pointed domain
- RHD:
-
runt homology domain
- SCF:
-
stem cell factor
- T/A:
-
TEL/AML1
- TAD:
-
transactivating domain
References
Akashi K, He X, Chen J, Iwasaki H, Niu C, Steenhard B, Zhang J, Haug J and Li L . (2003). Blood, 101, 383–390.
Bernardi R, Grisendi S and Pandolfi P . (2002). Oncogene, 21, 3445–3458.
Bernardin F, Yang Y, Cleaves R, Zahurak M, Cheng L, Civin C and Friedman A . (2002). Cancer Res., 62, 3904–3908.
Borkhardt A, Cazzaniga G, Viehmann S, Valsecchi M, Ludwig W, Burci L, Mangioni S, Schrappe M, Riehm H, Lampert F, Basso G, Masera G, Harbott J and Biondi A . (1997). Blood, 90, 571–577.
Christensen J and Weissman I . (2001). Proc. Natl. Acad. Sci. USA, 98, 14541–14546.
de Guzman C . (2002). Mol. Cell. Biol., 22, 5506–5517.
Elefanty AG and Cory S . (1992). Mol. Cell. Biol., 12, 1755–1763.
Erikson P, Gao J, Chang K-S, Look T, Whisenant E, Raimondi S, Lasher R, Trujillo J, Rowley J and Drabkin H . (1992). Blood, 80, 1825–1831.
Fenrick R, Amann J, Lutterbach B, Wang L, Westendorf J, Downing J and Hiebert S . (1999). Mol. Cell. Biol., 19, 6566–6574.
Fenrick R, Wang L, Nip J, Amann J, Rooney R, Walker-Daniels J, Crawford H, Hulboy D, Kinch M, Matrisian L and Hiebert S . (2000). Mol. Cell. Biol., 20, 5828–5839.
Golub T, Varker G, Bohlander S, Hiebert S, Ward C, Bray-Ward P, Morgan E, Raimondi S, Rowley J and Gilliland D . (1995). Proc. Natl. Acad. Sci. USA, 92, 4917–4921.
Gong J . (1978). Science, 199, 1443–1445.
Greaves M, Maia A, Wiemals J and Ford A . (2003). Blood, 102, 2321–2333.
Growney JD, Shigematsu H, Li Z, Lee BH, Adelsperger J, Rowan R, Curley DP, Kutok JL, Akashi K, Williams IR, Speck NA and Gilliland DG . (2005). Blood, 106, 494–504.
Hardy R, Carmack C, Shinton S, Kemp J and Hayakawa K . (1991). J. Exp. Med., 173, 1213–1225.
Hayashi K, Natsume W, Watanabe T, Abe N, Iwai N, Okada H, Ito Y, Asano M, Iwakura Y, Habu S, Takahama Y and Satake M . (2000). J. Immunol., 165, 6816–6824.
Hiebert S, Lutterbach B, Durst K, Wang L, Linggi B, Wu S, Wood L, Amann J, King D and Hou Y . (2001). Cancer Chemother. Pharmacol., 48 (Suppl1), S31–S34.
Higuchi M, ÓBrien D, Kumaravelu P, Lenny N, Yeoh E-J and Downing J . (2002). Cancer Cell, 1, 63–74.
Holtschke T, Löhler J, Kanno Y, Fehr T, Giese N, Rosenbauer F, Lou J, Knobeloch K-P, Gabriele L, Waring J, Bachmann M, Zinkernagel R, Morse III H, Ozato K and Horak I . (1996). Cell, 87, 307–317.
Ichikawa M, Asai T, Saito T, Yamamoto G, Seo S, Yamazaki I, Yamagata T, Mitani K, Chiba S, Hirai H, Ogawa S and Kurokawa M . (2004). Nat. Med., 10, 299–304.
Irvin B, Wood L, Wang L, Fenrick R, Sansam C, Packham G, Kinch M, Yang E and Hiebert S . (2003). J. Biol. Chem., 278, 46378–46386.
Jousset C, Carron C, Boureux A, Quang C, Oury C, Dusanter-Fourt I, Charon M, Levin J, Bernard O and Ghysdael J . (1997). EMBO J., 16, 69–82.
Kitabayashi I, Tokoyama A, Shimazu K and Ohki M . (1998). EMBO J., 17, 2994–3004.
Lagasse E, Shizuru J, Uchida N, Tsukamoto A and Weissman I . (2001). Immunity, 14, 425–436.
Lessard J and Sauvageau G . (2003). Nature, 423, 255–260.
Levanon D, Goldstein R, Bernstein Y, Tang H, Goldenberg D, Stifani S, Paroush Z and Groner Y . (1998). Proc. Natl. Acad. Sci. USA, 95, 11590–11595.
Li Z, Schwieger M, Lange C, Kraunus J, Sun H, van den Akker E, Modlich U, Serinsoz E, Will E, von Laer D, Stocking C, Fehse B, Schiedlmeier B and Baum C . (2003). J. Exp. Hematol., 31, 1206–1214.
Licht J . (2001). Oncogene, 20, 5660–5679.
Lopez R, Carron C, Oury C, Gardellin P, Bernard O and Ghysdael J . (1999). J. Biol. Chem., 274, 30132–30138.
McLean TW, Ringold S, Neuberg D, Stegmaier K, Tantravahi R, Ritz J, Koeffler HP, Takeuchi S, Janssen JW, Seriu T, Bartram CR, Sallan SE, Gilliland DG and Golub TR . (1996). Blood, 88, 4252–4258.
Meyer J, Jücker M, Ostertag W and Stocking C . (1998). Blood, 91, 1901–1908.
Meyers S, Downing J and Hiebert S . (1993). Mol. Cell. Biol., 13, 6336–6345.
Miyoshi H, Kozu T, Shimizu K, Enomoto K, Maseki N, Kaneko Y, Kamada N and Ohki M . (1993). EMBO J., 12, 2715–2721.
Mori H, Colman S, Xiao Z, Ford A, Healy L, Donaldson C, Hows J, Navarrete C and Greaves M . (2002). Proc. Natl. Acad. Sci. USA, 99, 8242–8247.
Morrison S, Wandycz A, Hemmati H, Wright D and Weissman I . (1997). Development, 124, 1929–1939.
Morrow M, Horton S, Kioussis D, Brady H and Williams O . (2004). Blood, 103, 3890–3896.
Muller-Tidow C, Steffen B, Cauvet T, Tickenbrock L, Ji P, Diederichs S, Sargin B, Kohler G, Stelljes M, Puccetti E, Ruthardt M, deVos S, Hiebert S, Koeffler H, Berdel W and Serve H . (2004). Mol. Cell. Biol., 24, 2890–2904.
Okada H, Watanabe T, Niki M, Takano H, Chiba N, Yanai N, Tani Hibino H, Asano S, Mucenski M, Ito Y, Noda T and Satake M . (1998). Oncogene, 17, 2287–2293.
Osato M . (2004). Oncogene, 23, 4284–4296.
Pabst T, Mueller B, Harakawa N, Schoch C, Haferlach T, Behre G, Hiddemann W, Zhang D-E and Tenen D . (2001). Nat. Med., 7, 1–8.
Petrovick M, Hiebert S, Friedman A, Hetherington C, Tenen D and Zhang D-E . (1998). Mol. Cell. Biol., 18, 3915–3925.
Putz G, Rosner A, Nuesslein I, Schmitz N and Buchholz F . (2005). Oncogene submitted.
Randall T and Weissman I . (1997). Blood, 89, 3596–3606.
Romana S, Mauchauffe M, LeConiat M, Chumakov I, LePalier D, Berger R and Bernard O . (1995). Blood, 85, 3662–3670.
Schebesta M, Heavey B and Busslinger M . (2002). Curr. Opin. Immunol., 14, 216–223.
Schwieger M, Löhler J, Friel J, Scheller M, Horak I and Stocking C . (2002). J. Exp. Med., 196, 1227–1240.
Shurtleff S, Buijs A, Behm F, Rubnitz J, Raimondi S, Hancock M, Chan G, Pui C, Grosveld G and Downing J . (1995). Leukemia, 9, 1985–1989.
Smith K, Chanda S, Lingbeek M, Ross D, Botstein D, van Lohuizen M and Cleary M . (2003). Mol. Cell, 12, 393–400.
Speck N and Gilliland D . (2002). Nat. Rev. Cancer, 2, 502–513.
Sun W and Downing JR . (2004). Blood, 104, 3565–3572.
Tenen D, Hromas T, Licht J and Zhang D-E . (1997). Blood, 90, 489–519.
Terskikh A, Miyamoto T, Chang C, Diatchenko L and Weissman I . (2003). Blood, 102, 94–101.
Tsuzuki S, Seto M, Greaves M and Enver T . (2004). Proc. Natl. Acad. Sci. USA, 101, 8443–8448.
van Rompaey L, Potter M, Adams C and Grosveld G . (2000). Oncogene, 19, 5244–5250.
Wang L and Hiebert S . (2001). Oncogene, 20, 3716–3725.
Westendorf J, Yamamoto C, Lenny N, Downing J, Selsted M and Hiebert S . (1998). Mol. Cell. Biol., 18, 323–333.
Yuan Y, Zhou L, Miyamato T, Iwasaki H, Harakawa N, Hetherington C, Burel S, Lagasse E, Weisman I, Akashi K and Zhang D-E . (2001). Proc. Natl. Acad. Sci. USA, 98, 10398–10403.
Zelent A, Greaves M and Enver T . (2004). Oncogene, 23, 4275–4283.
Zhang SL, DuBois W, Ramsay ES, Bliskovski V, Morse III HC, Taddesse-Heath L, Vass WC, DePinho RA and Mock BA . (2001). Mol. Cell. Biol., 21, 310–318.
Acknowledgements
We thank Drs J Cammenga and J Ghysdael for stimulating discussion and the latter for also providing the TEL/Sw plasmid. We also acknowledge the excellent technical support of Marion Ziegler and Karin Heigl, and Arne Düsedau for cell sorting. This work was part of the doctoral thesis of M Fischer, Department of Biology, University of Hamburg, Hamburg, Germany. This work was supported by a grant from the Deutsche José Carreras-Leukemia-Stiftung (RO1/04) and the Frtiz Thyssen Foundation (10.05.1.182). The Heinrich-Pette-Institut is supported by the Freie und Hansestadt Hamburg and the Bundesministerium für Gesundheit.
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Fischer, M., Schwieger, M., Horn, S. et al. Defining the oncogenic function of the TEL/AML1 (ETV6/RUNX1) fusion protein in a mouse model. Oncogene 24, 7579–7591 (2005). https://doi.org/10.1038/sj.onc.1208931
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DOI: https://doi.org/10.1038/sj.onc.1208931
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