title: SMYD2 lysine methyltransferase regulates leukemia cell growth and regeneration after genotoxic stress.
abstract: The molecular determinants governing escape of Acute Myeloid Leukemia (AML) cells from DNA damaging therapy remain poorly defined and account for therapy failures. To isolate genes responsible for leukemia cells regeneration following multiple challenges with irradiation we performed a genome-wide shRNA screen. Some of the isolated hits are known players in the DNA damage response (e.g. p53, CHK2), whereas other, e.g. SMYD2 lysine methyltransferase (KMT), remains uncharacterized in the AML context. Here we report that SMYD2 knockdown confers relative resistance to human AML cells against multiple classes of DNA damaging agents. Induction of the transient quiescence state upon SMYD2 downregulation correlated with the resistance. We revealed that diminished SMYD2 expression resulted in the upregulation of the related methyltransferase SET7/9, suggesting compensatory relationships. Indeed, pharmacological targeting of SET7/9 with (R)-PFI2 inhibitor preferentially inhibited the growth of cells expressing low levels of SMYD2.Finally, decreased expression of SMYD2 in AML patients correlated with the reduced sensitivity to therapy and lower probability to achieve complete remission. We propose that the interplay between SMYD2 and SET7/9 levels shifts leukemia cells from growth to quiescence state that is associated with the higher resistance to DNA damaging agents and rationalize SET7/9 pharmacological targeting in AML.
authors.affiliation: Department of Pathology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Adi
authors.initials: A
authors.lastname: Zipin-Roitman
authors.affiliation: Department of Pathology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Nasma
authors.initials: N
authors.lastname: Aqaqe
authors.affiliation: Department of Pathology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Yassin
authors.affiliation: Department of Pathology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Shahar
authors.initials: S
authors.lastname: Biechonski
authors.affiliation: Department of Pathology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Mariam
authors.initials: M
authors.lastname: Amar
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Canada.|Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia.
authors.forename: Mark F
authors.initials: MF
authors.lastname: van Delft
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Canada.|Department of Molecular Genetics, University of Toronto, Toronto, Canada.
authors.forename: Olga I
authors.initials: OI
authors.lastname: Gan
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Canada.|Leidos Biomedical Research, Washington D.C., USA.
authors.forename: Sean P
authors.initials: SP
authors.lastname: McDermott
authors.affiliation: Donnelly Centre for Cellular and Biomedical Research, University of Toronto, Toronto, Canada.|Department of Molecular Genetics, University of Toronto, Toronto, Canada.
authors.forename: Alla
authors.initials: A
authors.lastname: Buzina
authors.affiliation: Donnelly Centre for Cellular and Biomedical Research, University of Toronto, Toronto, Canada.|Department of Molecular Genetics, University of Toronto, Toronto, Canada.
authors.forename: Troy
authors.initials: T
authors.lastname: Ketela
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Canada.|Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Liran
authors.initials: L
authors.lastname: Shlush
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Canada.|Department of Molecular Genetics, University of Toronto, Toronto, Canada.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Xie
authors.affiliation: Donnelly Centre for Cellular and Biomedical Research, University of Toronto, Toronto, Canada.|Department of Molecular Genetics, University of Toronto, Toronto, Canada.
authors.forename: Veronique
authors.initials: V
authors.lastname: Voisin
authors.affiliation: Donnelly Centre for Cellular and Biomedical Research, University of Toronto, Toronto, Canada.|Department of Molecular Genetics, University of Toronto, Toronto, Canada.
authors.forename: Jason
authors.initials: J
authors.lastname: Moffat
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Canada.|Department of Medicine, University of Toronto, Toronto, Canada.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Minden
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Canada.|Department of Molecular Genetics, University of Toronto, Toronto, Canada.
authors.forename: John E
authors.initials: JE
authors.lastname: Dick
authors.affiliation: Department of Pathology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Michael
authors.initials: M
authors.lastname: Milyavsky
mesh_terms: D048708:Cell Growth Processes / Q000502:physiology; D004249:DNA Damage / Q000502:physiology; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D014162:Transfection
chemical_list: D034741:RNA, Small Interfering; D011495:Histone-Lysine N-Methyltransferase; C540312:SETD7 protein, human; C512569:SMYD2 protein, human
keywords: AML; DNA damage; SMYD2 lysine methyltransferase; chemotherapy; quiescence