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Defining the oncogenic function of the TEL/AML1 (ETV6/RUNX1) fusion protein in a mouse model

Oncogene volume 24, pages 7579–7591 (2005)Cite this article

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

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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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Authors and Affiliations

  1. Molecular Pathology Group, Heinrich-Pette-Institut für Experimentelle Immunologie und Virologie, Hamburg, D-20251, Germany

    Meike Fischer, Maike Schwieger, Stefan Horn, Birte Niebuhr, Susanne Roscher, Ulla Bergholz, Jürgen Löhler & Carol Stocking

  2. Leukemia Research Fund Centre at the Institute of Cancer Research, Chester Beatty Laboratories, London, SW3 6JB, UK

    Anthony Ford & Mel Greaves

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  1. Meike Fischer
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Correspondence to Carol Stocking.

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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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