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 retro...

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Bibliographic Details
Published in:Blood 2004-05, Vol.103 (10), p.3890-3896
Main Authors: Morrow, Michelle, Horton, Sarah, Kioussis, Dimitris, Brady, Hugh J.M., Williams, Owen
Format: Article
Language:English
Subjects:
Animals
B-Lymphocytes
Biological and medical sciences
Cell Lineage
Core Binding Factor Alpha 2 Subunit
Fetus - cytology
Hematologic and hematopoietic diseases
Hematopoiesis
Hematopoietic Stem Cell Transplantation
Hematopoietic Stem Cells - cytology
Hematopoietic Stem Cells - metabolism
Humans
Leukemia - etiology
Leukemia - pathology
Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis
Medical sciences
Mice
Mice, Inbred C57BL
Myeloid Cells
Oncogene Proteins, Fusion - genetics
Oncogene Proteins, Fusion - physiology
Preleukemia - etiology
Preleukemia - pathology
T-Lymphocytes
Transfection
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Summary: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.
ISSN:0006-4971
1528-0020
DOI:10.1182/blood-2003-10-3695