Analysis of the modulation of transcriptional activity in myelopoiesis andleukemogenesis

Citation
G. Behre et al., Analysis of the modulation of transcriptional activity in myelopoiesis andleukemogenesis, METHODS, 17(3), 1999, pp. 231-237
Citations number
60
Categorie Soggetti
Biochemistry & Biophysics
Journal title
METHODS-A COMPANION TO METHODS IN ENZYMOLOGY
ISSN journal
10462023 → ACNP
Volume
17
Issue
3
Year of publication
1999
Pages
231 - 237
Database
ISI
SICI code
1046-2023(199903)17:3<231:AOTMOT>2.0.ZU;2-B
Abstract
Acute myeloid leukemia (AML) is still associated with a mortality of 60 to 80%. AML is characterized by a block in myeloid differentiation. The transc ription factors PU.1 and C/EBP alpha are responsible for normal myeloid dif ferentiation from stem cells to monocytes or granulocytes. In particular, P U.1 induces expression of the macrophage colony-stimulating factor (M-CSF) receptor and the development of monocytes, whereas C/EBP alpha increases th e expression of the granulocyte colony-stimulating factor (G-CSF) receptor and leads to mature granulocytes. In AML, chromosomal aberrations result in oncoproteins such as AML1/ETO, PML/RAR alpha, or activated Ras, which can deregulate genes important for normal myelopoiesis. Thus, AML1/ETO can bind to the transcription factor C/EBP alpha, inhibit C/EBP alpha-dependent tra nscription, and block granulocytic differentiation. However, AML1/ETO can a lso synergize with the transcription factor AML1 to enhance the activity of the M-CSF receptor promoter. On the other hand, the PML/RAR alpha fusion p rotein causes transcriptional repression by recruiting the nuclear corepres sor (N-CoR) histone deacetylase complex to the DNA, which results in decrea sed histone acetylation and a repressive chromatin organization. Here we de scribe methods to investigate whether and how signaling agonists induce mye loid differentiation and how oncoproteins might cause AML by modulating the activity of transcription factors that are pivotal for normal myeloid deve lopment. (C) 1999 Academic Press.