@article{db2e06dbc7df4a0683ed97838d6a5658,
title = "Intrinsically disordered Meningioma-1 stabilizes the BAF complex to cause AML",
abstract = "Meningioma-1 (MN1) overexpression in AML is associated with poor prognosis, and forced expression of MN1 induces leukemia in mice. We sought to determine how MN1 causes AML. We found that overexpression of MN1 can be induced by translocations that result in hijacking of a downstream enhancer. Structure predictions revealed that the entire MN1 coding frame is disordered. We identified the myeloid progenitor-specific BAF complex as the key interaction partner of MN1. MN1 over-stabilizes BAF on enhancer chromatin, a function directly linked to the presence of a long polyQ-stretch within MN1. BAF over-stabilization at binding sites of transcription factors regulating a hematopoietic stem/progenitor program prevents the developmentally appropriate decommissioning of these enhancers and results in impaired myeloid differentiation and leukemia. Beyond AML, our data detail how the overexpression of a polyQ protein, in the absence of any coding sequence mutation, can be sufficient to cause malignant transformation.",
keywords = "AML, BAF, IDP, IDR, intrinsically disordered protein/region, leukemia, Meningioma-1, polyQ, SWI/SNF",
author = "Riedel, {Simone S.} and Congcong Lu and Xie, {Hongbo M.} and Kevin Nestler and Vermunt, {Marit W.} and Alexandra Lenard and Laura Bennett and Speck, {Nancy A.} and Ichiro Hanamura and Lessard, {Julie A.} and Blobel, {Gerd A.} and Garcia, {Benjamin A.} and Bernt, {Kathrin M.}",
note = "Funding Information: We thank Ivan Maillard, Vikram Paralkar, Patricia Ernst, Stuart Orkin, Scott Armstrong, Leonard Zon, and Martin Carroll for helpful discussions. We thank Ellen Zwaarthoff for providing the MN1 cDNA, Michael Heuser for providing HA-MN1, and Tanja Gruber for providing TY1-MN1. We thank Trevor Williams for providing Mn1+/− mice and Laura Bennett and Nancy Speck for help with timed matings and the isolation of fetal liver cells. We thank the animal and flow cores at the Children{\textquoteright}s Hospital of Philadelphia (CHOP) and the University of Pennsylvania, as well as the Mass Spec Core at the University of Colorado and the University of Pennsylvania. This work was supported by startup funds from the Division of Pediatric Oncology and the Abramson Cancer Research Center at The Children's Hospital of Philadelphia , funding from the Doris Duke Foundation ( 2014104 to K.M.B.), Hyundai Hope On Wheels (to K.M.B.), the Emerson Collective (to K.M.B.), NIH grant P01CA196539 (to B.A.G.), a Robert Arceci Award from the Leukemia and Lymphoma Society (to B.A.G.), an EMBO long-term fellowship (ALTF 540-2018 , to M.W.V.), the Children's Hospital of Philadelphia Foerderer Award (to S.S.R.), and the American Society of Hematology (ASH) (to S.S.R.). Funding Information: We thank Ivan Maillard, Vikram Paralkar, Patricia Ernst, Stuart Orkin, Scott Armstrong, Leonard Zon, and Martin Carroll for helpful discussions. We thank Ellen Zwaarthoff for providing the MN1 cDNA, Michael Heuser for providing HA-MN1, and Tanja Gruber for providing TY1-MN1. We thank Trevor Williams for providing Mn1+/? mice and Laura Bennett and Nancy Speck for help with timed matings and the isolation of fetal liver cells. We thank the animal and flow cores at the Children's Hospital of Philadelphia (CHOP) and the University of Pennsylvania, as well as the Mass Spec Core at the University of Colorado and the University of Pennsylvania. This work was supported by startup funds from the Division of Pediatric Oncology and the Abramson Cancer Research Center at The Children's Hospital of Philadelphia, funding from the Doris Duke Foundation (2014104 to K.M.B.), Hyundai Hope On Wheels (to K.M.B.), the Emerson Collective (to K.M.B.), NIH grant P01CA196539 (to B.A.G.), a Robert Arceci Award from the Leukemia and Lymphoma Society (to B.A.G.), an EMBO long-term fellowship (ALTF 540-2018, to M.W.V.), the Children's Hospital of Philadelphia Foerderer Award (to S.S.R.), and the American Society of Hematology (ASH) (to S.S.R.). Conceptualization, S.S.R. and K.M.B.; methodology, S.S.R. M.W.V. G.A.B. L.B. N.A.S. K.N. C.L. B.A.G. and K.M.B.; investigation, S.S.R. C.L. K.N. A.L. and M.W.V.; software, H.M.X.; formal analysis, S.S.R. C.L. M.W.V. and H.M.X.; resources, J.A.L. (Smarca4f/f mice and critical expertise) and I.H. (AMU-AML1 patient sample and critical expertise); visualization, S.S.R. M.W.V. and H.M.X.; writing ? original draft, S.S.R. and K.M.B.; writing ? review and editing, S.S.R. C.L. J.A.L. M.W.V. G.A.B. and K.M.B.; supervision, K.M.B. N.A.S. G.A.B. and B.A.G.; funding acquisition, S.S.R. B.A.G. and K.M.B. K.M.B. holds a patent on the use of DOT1L inhibitors for MN1 leukemia. K.M.B. has received research funding from Syndax and has previously consulted for Agios. I.H. received research funding from Bristol-Myers Squibb (BMS), Celgene, Merck Sharpe & Dohme (MSD), Astellas, Otsuka, Ono, Kyowa Kirin, Sanofi, Shionogi, Zenyaku, Daiichi Sankyo, Taiho, Takeda, Chugai, Eli Lilly, Nihon Shinyaku, Novartis, Pfizer, Fujimoto, Tanabe-Mitsubishi, Fukuyu Hospital, and Yamada Yohojo and received honoraria from or holds membership on an entity's board of directors, speaker's bureau, or its advisory committees for Celgene, Janssen, Takeda, Ono, BMS, Novartis, Daiichi Sankyo, Kyowa Kirin, Eisai, Nihon-Shinyaku, Pfizer, AbbVie, Otsuka, Shionogi, Mundi, CSL, and MSD. All other authors declare no competing interests. One or more of the authors of this paper self-identifies as an underrepresented ethnic minority in science. Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",
year = "2021",
month = jun,
day = "3",
doi = "10.1016/j.molcel.2021.04.014",
language = "English",
volume = "81",
pages = "2332--2348.e9",
journal = "Molecular Cell",
issn = "1097-2765",
number = "11",
}