Abstract |
The chromosomal translocation t(12; 22)(p13;q11) in human myeloid leukemia generates an MN1-TEL (meningioma 1-translocation-ETS-leukemia) fusion oncoprotein. This protein consists of N-terminal MN1 sequences, a transcriptional coactivator fused to C-terminal TEL sequences, an ETS (E26 transformation-specific) transcription factor. Enforced expression of MN1-TEL in multipotent hematopoietic progenitors in knock-in mice perturbed growth and differentiation of myeloid as well as lymphoid cells. Depending on obligatory secondary mutations, these mice developed T-cell lympholeukemia. Here we addressed the role of MN1-TEL in myeloid leukemogenesis using the same mouse model. Expression of MN1-TEL enhanced the growth of myeloid progenitors in an interleukin 3/ stem cell factor (IL-3/SCF)-dependent manner in vitro whereas 10% of MN1-TEL-expressing mice developed altered myelopoiesis with severe anemia after long latency. Coexpression of MN1-TEL and IL-3, but not SCF, rapidly caused a fatal myeloproliferative disease rather than acute myeloid leukemia (AML). Because MN1-TEL+ AML patient cells overexpress HOXA9 (homeobox A9), we tested the effect of coexpression of MN1-TEL and HOXA9 in mice and found that 90% of MN1-TEL+/HOXA9+ mice developed AML much more rapidly than control HOXA9+ mice. Thus, the leukemogenic effect of MN1-TEL in our knock-in mice is pleiotropic, and the type of secondary mutation determines disease outcome.
|
Authors | Hiroyuki Kawagoe, Gerard C Grosveld |
Journal | Blood
(Blood)
Vol. 106
Issue 13
Pg. 4269-77
(Dec 15 2005)
ISSN: 0006-4971 [Print] United States |
PMID | 16105979
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
|
Chemical References |
- Cytokines
- ETS translocation variant 6 protein
- Homeodomain Proteins
- Mn1 protein, mouse
- Oncogene Proteins
- Proto-Oncogene Proteins c-ets
- Proto-Oncogene Proteins c-myc
- Repressor Proteins
- Trans-Activators
- Tumor Suppressor Proteins
- homeobox protein HOXA9
|
Topics |
- Animals
- Cell Proliferation
- Cells, Cultured
- Cytokines
(pharmacology)
- Gene Expression Regulation, Neoplastic
- Homeodomain Proteins
(genetics, metabolism)
- Humans
- Leukemia, Myeloid, Acute
(genetics, metabolism, pathology)
- Mice
- Mice, Transgenic
- Myeloid Progenitor Cells
(cytology, drug effects, metabolism)
- Oncogene Proteins
(genetics, metabolism)
- Proto-Oncogene Proteins c-ets
(genetics, metabolism)
- Proto-Oncogene Proteins c-myc
(metabolism)
- Repressor Proteins
(genetics, metabolism)
- Trans-Activators
- Transgenes
(genetics)
- Tumor Suppressor Proteins
|