MOZ-TIF2-induced acute myeloid leukemia requires the MOZ nucleosome binding motif and TIF2-mediated recruitment of CBP.
The MOZ-TIF2 fusion is associated with acute myeloid leukemia (AML) with inv(8)(p11q13). MOZ is a MYST family histone acetyltransferase (HAT), whereas TIF2 is a nuclear receptor coactivator that associates with CREB binding protein (CBP). Here we demonstrate that MOZ-TIF2 has transforming properties in vitro and causes AML in a murine bone marrow transplant assay. The C2HC nucleosome recognition motif of MOZ is essential for transformation, whereas MOZ HAT activity is dispensable. However, MOZ-TIF2 interaction with CBP through the TIF2 CBP interaction domain (CID) is essential for transformation. These results indicate that nucleosomal targeting by MOZ and recruitment of CBP by TIF2 are critical requirements for MOZ-TIF2 transformation and indicate that MOZ gain of function contributes to leukemogenesis.
Deguchi
Kenji
K
Division of Hematology and Oncology, Brigham and Women's Hospital and Harvard Medical School, Harvard Institutes, of Medicine, 4 Blackfan Circle, Room 420, Boston, MA 02115, USA.
Ayton
Paul M
PM
Carapeti
Melina
M
Kutok
Jeffery L
JL
Snyder
Cynthia S
CS
Williams
Ifor R
IR
Cross
Nicholas C P
NC
Glass
Christopher K
CK
Cleary
Michael L
ML
Gilliland
D Gary
DG
D000123:Acetyltransferases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016026:Bone Marrow Transplantation; D002460:Cell Line; D002472:Cell Transformation, Viral; D007446:Chromosome Inversion; D002898:Chromosomes, Human, Pair 8; D017362:Cyclic AMP Response Element-Binding Protein; D018380:Hematopoietic Stem Cell Transplantation; D051548:Histone Acetyltransferases; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D051379:Mice; D008958:Models, Molecular; D009687:Nuclear Proteins / Q000235:genetics; D051958:Nuclear Receptor Coactivator 2; D009707:Nucleosomes / Q000737:chemistry / Q000378:metabolism*; D017354:Point Mutation; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016335:Zinc Fingers / Q000235:genetics
D017362:Cyclic AMP Response Element-Binding Protein; C498001:NCOA2 protein, human; C498002:Ncoa2 protein, mouse; D009687:Nuclear Proteins; D051958:Nuclear Receptor Coactivator 2; D009707:Nucleosomes; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D000123:Acetyltransferases; D051548:Histone Acetyltransferases; C108712:KAT6A protein, human