Common themes in the pathogenesis of acute myeloid leukemia.
The pathogenesis of acute myeloid leukemia is associated with the appearance of oncogenic fusion proteins generated as a consequence of specific chromosome translocations. Of the two components of each fusion protein, one is generally a transcription factor, whereas the other partner is more variable in function, but often involved in the control of cell survival and apoptosis. As a consequence, AML-associated fusion proteins function as aberrant transcriptional regulators that interfere with the process of myeloid differentiation, determine a stage-specific arrest of maturation and enhance cell survival in a cell-type specific manner. The abnormal regulation of transcriptional networks occurs through common mechanisms that include recruitment of aberrant co-repressor complexes, alterations in chromatin remodeling, and disruption of specific subnuclear compartments. The identification and analysis of common and specific target genes regulated by AML fusion proteins will be of fundamental importance for the full understanding of acute myeloid leukemogenesis and for the implementation of disease-specific drug design.
Alcalay
M
M
Department of Experimental Oncology, European Institute of Oncology, 20141 Milan, Italy. malcalay@ieo.it
Orleth
A
A
Sebastiani
C
C
Meani
N
N
Chiaradonna
F
F
Casciari
C
C
Sciurpi
M T
MT
Gelmetti
V
V
Riganelli
D
D
Minucci
S
S
Fagioli
M
M
Pelicci
P G
PG
D002454:Cell Differentiation; D002470:Cell Survival; D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006410:Hematopoiesis; D006720:Homozygote; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000209:etiology* / Q000235:genetics* / Q000473:pathology*; D008954:Models, Biological; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D014178:Translocation, Genetic
D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins; D015514:Oncogene Proteins, Fusion; D011518:Proto-Oncogene Proteins; C493728:RUNX1 protein, human; D014157:Transcription Factors