Conditional MLL-CBP targets GMP and models therapy-related myeloproliferative disease.
EMBO J
; 24(2): 368-81, 2005 Jan 26.
Article
in En
| MEDLINE
| ID: mdl-15635450
ABSTRACT
Chromosomal translocations that fuse the mixed lineage leukemia (MLL) gene with multiple partners typify acute leukemias of infancy as well as therapy-related leukemias. We utilized a conditional knockin strategy to bypass the embryonic lethality caused by MLL-CBP expression and to assess the immediate effects of induced MLL-CBP expression on hematopoiesis. Within days of activating MLL-CBP, the fusion protein selectively expanded granulocyte/macrophage progenitors (GMP) and enhanced their self-renewal/proliferation. MLL-CBP altered the gene expression program of GMP, upregulating a subset of genes including Hox a9. Inhibition of Hox a9 expression by RNA interference demonstrated that MLL-CBP required Hox a9 for its enhanced cell expansion. Following exposure to sublethal gamma-irradiation or N-ethyl-N-nitrosourea (ENU), MLL-CBP mice developed myelomonocytic hyperplasia and progressed to fatal myeloproliferative disorders. These represented the spectrum of therapy-induced acute myelomonocytic leukemia/chronic myelomonocytic leukemia/myelodysplastic/myeloproliferative disorder similar to that seen in humans possessing the t(11;16). This model of MLL-CBP therapy-related myeloproliferative disease demonstrates the selectivity of this MLL fusion for GMP cells and its ability to initiate leukemogenesis in conjunction with cooperating mutations.
Full text:
1
Database:
MEDLINE
Main subject:
Transcription Factors
/
Proto-Oncogenes
/
Nuclear Proteins
/
Trans-Activators
/
DNA-Binding Proteins
/
Myeloproliferative Disorders
Type of study:
Prognostic_studies
Limits:
Animals
Language:
En
Year:
2005
Type:
Article