title: The downregulation of BAP1 expression by BCR-ABL reduces the stability of BRCA1 in chronic myeloid leukemia.
abstract: BCR-ABL induces an intrinsic genetic instability in chronic myeloid leukemia (CML). The protein breast cancer 1, early onset (BRCA1)-associated protein 1 (BAP1) is a deubiquitinase interacting with the DNA repair regulator BRCA1 and is frequently inactivated in many cancers. Here, we report that BAP1 mRNA and protein levels are downregulated in a BCR-ABL1-expressing hematopoietic cell line (UT-7/11). A decrease of BAP1 transcripts is also observed in newly diagnosed CML patients. Moreover, BAP1 protein levels are low or undetectable in CD34(+) cells from CML patients at diagnosis as compared with CD34(+) cells from normal donors. In addition, BRCA1 protein level is reduced in BCR-ABL1-expressing UT-7/11 cells. Finally, the enforced expression of BAP1 is associated with BRCA1 protein deubiquitination and restoration. These results demonstrate BAP1 as a major link with the BCR-ABL-induced downregulation of BRCA1 in CML.
authors.affiliation: Institut national U935 de la santé et de la recherche médicale, Université de Poitiers, Poitiers, France; Laboratoire Epigénétique et Destin Cellulaire, CNRS-UMR 7216 Université Paris Diderot, Sorbonne Paris Cité, Paris, France; Laboratoire Signalisation et Transports Ioniques Membranaires, CNRS-ERL 7368 Université de Poitiers, Poitiers, France. Electronic address: fatima.dkhissi@univ-poitiers.fr.
authors.forename: Fatima
authors.initials: F
authors.lastname: Dkhissi
authors.affiliation: Institut national U935 de la santé et de la recherche médicale, Université de Poitiers, Poitiers, France.
authors.forename: Djamel
authors.initials: D
authors.lastname: Aggoune
authors.affiliation: Laboratoire Epigénétique et Destin Cellulaire, CNRS-UMR 7216 Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Pontis
authors.affiliation: Institut national U935 de la santé et de la recherche médicale, Université de Poitiers, Poitiers, France; Service de Cancérologie Biologique, Centre Hospitalier Universitaire, Poitiers, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Sorel
authors.affiliation: Institut national U935 de la santé et de la recherche médicale, Université de Poitiers, Poitiers, France; Service de Cancérologie Biologique, Centre Hospitalier Universitaire, Poitiers, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Piccirilli
authors.affiliation: Institut national U935 de la santé et de la recherche médicale, Université de Poitiers, Poitiers, France.
authors.forename: Amélie
authors.initials: A
authors.lastname: LeCorf
authors.affiliation: Institut national U935 de la santé et de la recherche médicale, Université de Poitiers, Poitiers, France; Institut national CIC 1402 de la santé et de la recherche médicale, Centre Hospitalier Universitaire, Poitiers, France.
authors.forename: François
authors.initials: F
authors.lastname: Guilhot
authors.affiliation: Institut national U935 de la santé et de la recherche médicale, Université de Poitiers, Poitiers, France; Service de Cancérologie Biologique, Centre Hospitalier Universitaire, Poitiers, France.
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Chomel
authors.affiliation: Laboratoire Epigénétique et Destin Cellulaire, CNRS-UMR 7216 Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
authors.forename: Slimane
authors.initials: S
authors.lastname: Ait-Si-Ali
authors.affiliation: Institut national U935 de la santé et de la recherche médicale, Université de Poitiers, Poitiers, France; Institut national U935 de la santé et de la recherche médicale, Hôpitaux Universitaires Paris Sud Bicêtre, Université Paris-Sud 11, Paris, France. Electronic address: turviv33@gmail.com.
authors.forename: Ali G
authors.initials: AG
authors.lastname: Turhan
mesh_terms: D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D015536:Down-Regulation; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism*; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D055550:Protein Stability; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis* / Q000235:genetics; D043222:Ubiquitin Thiolesterase / Q000096:biosynthesis* / Q000235:genetics
chemical_list: C400134:BAP1 protein, human; D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D025521:Tumor Suppressor Proteins; D016044:Fusion Proteins, bcr-abl; D043222:Ubiquitin Thiolesterase