SMYD2 lysine methyltransferase regulates leukemia cell growth and regeneration after genotoxic stress
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Adi Zipin-Roitman1, Nasma Aqaqe1, Muhammad Yassin1, Shahar Biechonski1, Mariam Amer1, Mark F. van Delft2,3, Olga I. Gan2,8, Sean P. McDermott2,4, Alla Buzina6,8, Troy Ketela6,8, Liran Shlush2,5, Stephanie Xie2,8, Veronique Voisin6,8, Jason Moffat6,8, Mark D. Minden7,9, John E. Dick2,8, Michael Milyavsky1
1Department of Pathology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
2Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Canada
3Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia
4Leidos Biomedical Research, Washington D.C., USA
5Department of Immunology, Weizmann Institute of Science, Rehovot, Israel
6Donnelly Centre for Cellular and Biomedical Research, University of Toronto, Toronto, Canada
7Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Canada
8Department of Molecular Genetics, University of Toronto, Toronto, Canada
9Department of Medicine, University of Toronto, Toronto, Canada
Michael Milyavsky, email: email@example.com
Keywords: SMYD2 lysine methyltransferase, AML, quiescence, chemotherapy, DNA damage
Received: November 23, 2016 Accepted: January 24, 2017 Published: February 06, 2017
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.
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