title: Targeting the MLL complex in castration-resistant prostate cancer.
abstract: Resistance to androgen deprivation therapies and increased androgen receptor (AR) activity are major drivers of castration-resistant prostate cancer (CRPC). Although prior work has focused on targeting AR directly, co-activators of AR signaling, which may represent new therapeutic targets, are relatively underexplored. Here we demonstrate that the mixed-lineage leukemia protein (MLL) complex, a well-known driver of MLL fusion-positive leukemia, acts as a co-activator of AR signaling. AR directly interacts with the MLL complex via the menin-MLL subunit. Menin expression is higher in CRPC than in both hormone-naive prostate cancer and benign prostate tissue, and high menin expression correlates with poor overall survival of individuals diagnosed with prostate cancer. Treatment with a small-molecule inhibitor of menin-MLL interaction blocks AR signaling and inhibits the growth of castration-resistant tumors in vivo in mice. Taken together, this work identifies the MLL complex as a crucial co-activator of AR and a potential therapeutic target in advanced prostate cancer.
authors.affiliation: 1] Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan, USA. [2] Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Rohit
authors.initials: R
authors.lastname: Malik
authors.affiliation: 1] Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan, USA. [2] Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Amjad P
authors.initials: AP
authors.lastname: Khan
authors.affiliation: 1] Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan, USA. [2] Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Irfan A
authors.initials: IA
authors.lastname: Asangani
authors.affiliation: 1] Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan, USA. [2] Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Marcin
authors.initials: M
authors.lastname: Cieślik
authors.affiliation: 1] Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan, USA. [2] Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Prensner
authors.affiliation: 1] Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan, USA. [2] Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Xiaoju
authors.initials: X
authors.lastname: Wang
authors.affiliation: 1] Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan, USA. [2] Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Matthew K
authors.initials: MK
authors.lastname: Iyer
authors.affiliation: 1] Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan, USA. [2] Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Xia
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Dmitry
authors.initials: D
authors.lastname: Borkin
authors.affiliation: 1] Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan, USA. [2] Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: June
authors.initials: J
authors.lastname: Escara-Wilke
authors.affiliation: 1] Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan, USA. [2] Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Rachell
authors.initials: R
authors.lastname: Stender
authors.affiliation: 1] Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan, USA. [2] Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Yi-Mi
authors.initials: YM
authors.lastname: Wu
authors.affiliation: Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Yashar S
authors.initials: YS
authors.lastname: Niknafs
authors.affiliation: 1] Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan, USA. [2] Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Jing
authors.affiliation: 1] Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan, USA. [2] Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Qiao
authors.affiliation: 1] Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan, USA. [2] Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA. [3] Department of Urology, Henry Ford Health System, Detroit, Michigan, USA.
authors.forename: Nallasivam
authors.initials: N
authors.lastname: Palanisamy
authors.affiliation: 1] Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan, USA. [2] Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA. [3] Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Lakshmi P
authors.initials: LP
authors.lastname: Kunju
authors.affiliation: Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Pranathi M
authors.initials: PM
authors.lastname: Krishnamurthy
authors.affiliation: Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Anastasia K
authors.initials: AK
authors.lastname: Yocum
authors.affiliation: 1] Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA. [2] Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Dattatreya
authors.initials: D
authors.lastname: Mellacheruvu
authors.affiliation: 1] Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan, USA. [2] Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA. [3] Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Alexey I
authors.initials: AI
authors.lastname: Nesvizhskii
authors.affiliation: 1] Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan, USA. [2] Howard Hughes Medical Institute, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Xuhong
authors.initials: X
authors.lastname: Cao
authors.affiliation: 1] Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan, USA. [2] Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Saravana M
authors.initials: SM
authors.lastname: Dhanasekaran
authors.affiliation: 1] Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan, USA. [2] Radiation Oncology, University of Michigan, Ann Arbor, Michigan, USA. [3] Department of Urology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Felix Y
authors.initials: FY
authors.lastname: Feng
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Jolanta
authors.initials: J
authors.lastname: Grembecka
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Cierpicki
authors.affiliation: 1] Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan, USA. [2] Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA. [3] Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan, USA. [4] Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA. [5] Howard Hughes Medical Institute, University of Michigan, Ann Arbor, Michigan, USA. [6] Department of Urology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Arul M
authors.initials: AM
authors.lastname: Chinnaiyan
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D051788:Myeloid-Lymphoid Leukemia Protein / Q000378:metabolism*; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D011471:Prostatic Neoplasms; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D011944:Receptors, Androgen / Q000378:metabolism*; D015398:Signal Transduction; D016896:Treatment Outcome
chemical_list: C410798:AR protein, human; C497422:KMT2A protein, human; C105373:MEN1 protein, human; C484898:Men1 protein, mouse; D011518:Proto-Oncogene Proteins; D011944:Receptors, Androgen; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; C497423:Kmt2a protein, mouse
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