Concurrent transcriptional deregulation of AML1/RUNX1 and GATA factors by the AML1-TRPS1 chimeric gene in t(8;21)(q24;q22) acute myeloid leukemia.
The Runt domain transcription factor AML1/RUNX1 is essential for the generation of hematopoietic stem cells and is the most frequent target of chromosomal translocations associated with leukemia. Here, we present a new AML1 translocation found in a patient with acute myeloid leukemia M4 with t(8;21)(q24;q22) at the time of relapse. This translocation generated an in-frame chimeric gene consisting of the N-terminal portion of AML1, retaining the Runt domain, fused to the entire length of TRPS1 on the C-terminus. TRPS1 encodes a putative multitype zinc finger (ZF) protein containing 9 C2H2 type ZFs and 1 GATA type ZF. AML1-TRPS1 stimulated proliferation of hematopoietic colony-forming cells and repressed the transcriptional activity of AML1 and GATA-1 by 2 different mechanisms: competition at their cognate DNA-binding sites and physical sequestrations of AML1 and GATA-1, suggesting that simultaneous deregulation of AML1 and GATA factors constitutes a basis for leukemogenesis.
Asou
Norio
N
Department of Hematology, Kumamoto University School of Medicine, 1-1-1 Honjo, Kumamoto 860-8556, Japan. ktcnasou@gpo.kumamoto-u.ac.jp
Yanagida
Masatoshi
M
Huang
Liqun
L
Yamamoto
Masayuki
M
Shigesada
Katsuya
K
Mitsuya
Hiroaki
H
Ito
Yoshiaki
Y
Osato
Motomi
M
D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics / Q000378:metabolism; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics / Q000378:metabolism; D050676:Core Binding Factor Alpha 2 Subunit / Q000096:biosynthesis* / Q000235:genetics; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D050980:GATA Transcription Factors / Q000235:genetics / Q000378:metabolism*; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D015514:Oncogene Proteins, Fusion / Q000096:biosynthesis* / Q000235:genetics; D012097:Repressor Proteins; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D014158:Transcription, Genetic; D014178:Translocation, Genetic / Q000235:genetics
D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins; D050980:GATA Transcription Factors; D015514:Oncogene Proteins, Fusion; C493728:RUNX1 protein, human; D012097:Repressor Proteins; C108387:TRPS1 protein, human; D014157:Transcription Factors