AI Article Synopsis

  • The study identifies genes that help Acute Myeloid Leukemia (AML) cells survive DNA damaging therapies, with a focus on the role of SMYD2.
  • SMYD2 knockdown makes AML cells more resistant to DNA damaging agents and leads to a state of temporary dormancy, suggesting it plays a critical role in treatment outcomes.
  • The research highlights a compensatory relationship between SMYD2 and another methyltransferase, SET7/9, indicating that targeting SET7/9 could be a promising strategy to improve therapy effectiveness in AML.

Article 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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5369996PMC
http://dx.doi.org/10.18632/oncotarget.15147DOI Listing

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