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

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(+)/Kit(hi)/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.

journal_name

Oncogene

journal_title

Oncogene

authors

Fischer M,Schwieger M,Horn S,Niebuhr B,Ford A,Roscher S,Bergholz U,Greaves M,Löhler J,Stocking C

doi

10.1038/sj.onc.1208931

subject

Has Abstract

pub_date

2005-11-17 00:00:00

pages

7579-91

issue

51

eissn

0950-9232

issn

1476-5594

pii

1208931

journal_volume

24

pub_type

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