Defining the oncogenic function of the TEL/AML1 (ETV6/RUNX1) fusion protein in a mouse model.
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.
Fischer
Meike
M
Molecular Pathology Group, Heinrich-Pette-Institut für Experimentelle Immunologie und Virologie, D-20251 Hamburg, Germany.
Schwieger
Maike
M
Horn
Stefan
S
Niebuhr
Birte
B
Ford
Anthony
A
Roscher
Susanne
S
Bergholz
Ulla
U
Greaves
Mel
M
Löhler
Jürgen
J
Stocking
Carol
C
D000818:Animals; D001402:B-Lymphocytes; D016026:Bone Marrow Transplantation; D002454:Cell Differentiation; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002881:Chromosomes, Human, Pair 12; D002891:Chromosomes, Human, Pair 21; D050676:Core Binding Factor Alpha 2 Subunit / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D006412:Hematopoietic Stem Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D015514:Oncogene Proteins, Fusion / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D010641:Phenotype; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics; D011289:Preleukemia / Q000235:genetics* / Q000503:physiopathology; D014178:Translocation, Genetic; D000097764:ETS Translocation Variant 6 Protein
D050676:Core Binding Factor Alpha 2 Subunit; D015514:Oncogene Proteins, Fusion; C493728:RUNX1 protein, human; C102421:TEL-AML1 fusion protein; D000097764:ETS Translocation Variant 6 Protein