TY - JOUR
T1 - Loss of the tumor suppressor BAP1 causes myeloid transformation
AU - Dey, Anwesha
AU - Seshasayee, Dhaya
AU - Noubade, Rajkumar
AU - French, Dorothy M.
AU - Liu, Jinfeng
AU - Chaurushiya, Mira S.
AU - Kirkpatrick, Donald S.
AU - Pham, Victoria C.
AU - Lill, Jennie R.
AU - Bakalarski, Corey E.
AU - Wu, Jiansheng
AU - Phu, Lilian
AU - Katavolos, Paula
AU - LaFave, Lindsay M.
AU - Abdel-Wahab, Omar
AU - Modrusan, Zora
AU - Seshagiri, Somasekar
AU - Dong, Ken
AU - Lin, Zhonghua
AU - Balazs, Mercedesz
AU - Suriben, Rowena
AU - Newton, Kim
AU - Hymowitz, Sarah
AU - Garcia-Manero, Guillermo
AU - Martin, Flavius
AU - Levine, Ross L.
AU - Dixit, Vishva M.
PY - 2012/9/21
Y1 - 2012/9/21
N2 - De-ubiquitinating enzyme BAP1 is mutated in a hereditary cancer syndrome with increased risk of mesothelioma and uveal melanoma. Somatic BAP1 mutations occur in various malignancies. We show that mouse Bap1 gene deletion is lethal during embryogenesis, but systemic or hematopoietic-restricted deletion in adults recapitulates features of human myelodysplastic syndrome (MDS). Knockin mice expressing BAP1 with a 3xFlag tag revealed that BAP1 interacts with host cell factor-1 (HCF-1), O-linked N-acetylglucosamine transferase (OGT), and the polycomb group proteins ASXL1 and ASXL2 in vivo. OGT and HCF-1 levels were decreased by Bap1 deletion, indicating a critical role for BAP1 in stabilizing these epigenetic regulators. Human ASXL1 is mutated frequently in chronic myelomonocytic leukemia (CMML) so an ASXL/BAP1 complex may suppress CMML. A BAP1 catalytic mutation found in a MDS patient implies that BAP1 loss of function has similar consequences in mice and humans.
AB - De-ubiquitinating enzyme BAP1 is mutated in a hereditary cancer syndrome with increased risk of mesothelioma and uveal melanoma. Somatic BAP1 mutations occur in various malignancies. We show that mouse Bap1 gene deletion is lethal during embryogenesis, but systemic or hematopoietic-restricted deletion in adults recapitulates features of human myelodysplastic syndrome (MDS). Knockin mice expressing BAP1 with a 3xFlag tag revealed that BAP1 interacts with host cell factor-1 (HCF-1), O-linked N-acetylglucosamine transferase (OGT), and the polycomb group proteins ASXL1 and ASXL2 in vivo. OGT and HCF-1 levels were decreased by Bap1 deletion, indicating a critical role for BAP1 in stabilizing these epigenetic regulators. Human ASXL1 is mutated frequently in chronic myelomonocytic leukemia (CMML) so an ASXL/BAP1 complex may suppress CMML. A BAP1 catalytic mutation found in a MDS patient implies that BAP1 loss of function has similar consequences in mice and humans.
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U2 - 10.1126/science.1221711
DO - 10.1126/science.1221711
M3 - Article
AN - SCOPUS:84866467141
SN - 0036-8075
VL - 337
SP - 1541
EP - 1546
JO - Science
JF - Science
IS - 6101
ER -
