title: Identification of regulators of polyploidization presents therapeutic targets for treatment of AMKL.
abstract: The mechanism by which cells decide to skip mitosis to become polyploid is largely undefined. Here we used a high-content image-based screen to identify small-molecule probes that induce polyploidization of megakaryocytic leukemia cells and serve as perturbagens to help understand this process. Our study implicates five networks of kinases that regulate the switch to polyploidy. Moreover, we find that dimethylfasudil (diMF, H-1152P) selectively increased polyploidization, mature cell-surface marker expression, and apoptosis of malignant megakaryocytes. An integrated target identification approach employing proteomic and shRNA screening revealed that a major target of diMF is Aurora kinase A (AURKA). We further find that MLN8237 (Alisertib), a selective inhibitor of AURKA, induced polyploidization and expression of mature megakaryocyte markers in acute megakaryocytic leukemia (AMKL) blasts and displayed potent anti-AMKL activity in vivo. Our findings provide a rationale to support clinical trials of MLN8237 and other inducers of polyploidization and differentiation in AMKL.
authors.affiliation: Division of Hematology/Oncology, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Wen
authors.forename: Benjamin
authors.initials: B
authors.lastname: Goldenson
authors.forename: Serena J
authors.initials: SJ
authors.lastname: Silver
authors.forename: Monica
authors.initials: M
authors.lastname: Schenone
authors.forename: Vlado
authors.initials: V
authors.lastname: Dancik
authors.forename: Zan
authors.initials: Z
authors.lastname: Huang
authors.forename: Ling-Zhi
authors.initials: LZ
authors.lastname: Wang
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Lewis
authors.forename: W Frank
authors.initials: WF
authors.lastname: An
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Li
authors.forename: Mark-Anthony
authors.initials: MA
authors.lastname: Bray
authors.forename: Clarisse
authors.initials: C
authors.lastname: Thiollier
authors.forename: Lauren
authors.initials: L
authors.lastname: Diebold
authors.forename: Laure
authors.initials: L
authors.lastname: Gilles
authors.forename: Martha S
authors.initials: MS
authors.lastname: Vokes
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Moore
authors.forename: Meghan
authors.initials: M
authors.lastname: Bliss-Moreau
authors.forename: Lynn
authors.initials: L
authors.lastname: Verplank
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Tolliday
authors.forename: Rama
authors.initials: R
authors.lastname: Mishra
authors.forename: Sasidhar
authors.initials: S
authors.lastname: Vemula
authors.forename: Jianjian
authors.initials: J
authors.lastname: Shi
authors.forename: Lei
authors.initials: L
authors.lastname: Wei
authors.forename: Reuben
authors.initials: R
authors.lastname: Kapur
authors.forename: Cécile K
authors.initials: CK
authors.lastname: Lopez
authors.forename: Bastien
authors.initials: B
authors.lastname: Gerby
authors.forename: Paola
authors.initials: P
authors.lastname: Ballerini
authors.forename: Francoise
authors.initials: F
authors.lastname: Pflumio
authors.forename: D Gary
authors.initials: DG
authors.lastname: Gilliland
authors.forename: Liat
authors.initials: L
authors.lastname: Goldberg
authors.forename: Yehudit
authors.initials: Y
authors.lastname: Birger
authors.forename: Shai
authors.initials: S
authors.lastname: Izraeli
authors.forename: Alan S
authors.initials: AS
authors.lastname: Gamis
authors.forename: Franklin O
authors.initials: FO
authors.lastname: Smith
authors.forename: William G
authors.initials: WG
authors.lastname: Woods
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Taub
authors.forename: Christina A
authors.initials: CA
authors.lastname: Scherer
authors.forename: James E
authors.initials: JE
authors.lastname: Bradner
authors.forename: Boon-Cher
authors.initials: BC
authors.lastname: Goh
authors.forename: Thomas
authors.initials: T
authors.lastname: Mercher
authors.forename: Anne E
authors.initials: AE
authors.lastname: Carpenter
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Gould
authors.forename: Paul A
authors.initials: PA
authors.lastname: Clemons
authors.forename: Steven A
authors.initials: SA
authors.lastname: Carr
authors.forename: David E
authors.initials: DE
authors.lastname: Root
authors.forename: Stuart L
authors.initials: SL
authors.lastname: Schreiber
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Stern
authors.forename: John D
authors.initials: JD
authors.lastname: Crispino
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D064096:Aurora Kinase A; D064127:Aurora Kinases; D001381:Azepines / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D055808:Drug Discovery; D006801:Humans; D007947:Leukemia, Megakaryoblastic, Acute / Q000188:drug therapy* / Q000235:genetics; D008533:Megakaryocytes / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D011123:Polyploidy; D060066:Protein Interaction Maps; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D054852:Small Molecule Libraries; D054460:rho-Associated Kinases / Q000378:metabolism
chemical_list: C459092:2-methyl-1-((4-methyl-5-isoquinolinyl)sulfonyl)homopiperazine; D001381:Azepines; C550258:MLN 8237; D011743:Pyrimidines; D054852:Small Molecule Libraries; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; C576917:AURKA protein, human; C576918:Aurka protein, mouse; D064096:Aurora Kinase A; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases