TEL-AML1 promotes development of specific hematopoietic lineages consistent with preleukemic activity.
The t(12;21)(p13;q22) translocation is the most common chromosomal abnormality yet identified in any pediatric leukemia and gives rise to the TEL-AML1 fusion product. To investigate the effects of TEL-AML1 on hematopoiesis, fetal liver hematopoietic progenitor cells (HPCs) were transduced with retroviral vectors expressing this fusion protein. We show that TEL-AML1 dramatically alters differentiation of HPCs in vitro, preferentially promoting B-lymphocyte development, enhancing self-renewal of B-cell precursors, and leading to the establishment of long-term growth factor-dependent pre-B-cell lines. However, it had no effect on myeloid development in vitro. Further experiments were performed to determine whether TEL-AML1 also demonstrates lineage-specific activity in vivo. TEL-AML1-expressing HPCs displayed a competitive advantage in reconstituting both B-cell and myeloid lineages in vivo but had no effect on reconstitution of the T-cell lineage. Despite promoting these alterations in hematopoiesis, TEL-AML1 did not induce leukemia in transplanted mice. Our study provides a unique insight into the role of TEL-AML1 in leukemia predisposition and a potential model to study the mechanism of leukemogenesis associated with this fusion.
Morrow
Michelle
M
Molecular Haematology and Cancer Biology Unit, Institute of Child Health, University College London, London, United Kingdom.
Horton
Sarah
S
Kioussis
Dimitris
D
Brady
Hugh J M
HJ
Williams
Owen
O
D000818:Animals; D001402:B-Lymphocytes; D019070:Cell Lineage; D050676:Core Binding Factor Alpha 2 Subunit; D005333:Fetus / Q000166:cytology; D006410:Hematopoiesis; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism; D006801:Humans; D007938:Leukemia / Q000209:etiology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000502:physiology*; D011289:Preleukemia / Q000209:etiology* / Q000473:pathology; D013601:T-Lymphocytes; D014162:Transfection; D000097764:ETS Translocation Variant 6 Protein
D050676:Core Binding Factor Alpha 2 Subunit; D015514:Oncogene Proteins, Fusion; C102421:TEL-AML1 fusion protein; D000097764:ETS Translocation Variant 6 Protein