SMYD2 lysine methyltransferase regulates leukemia cell growth and regeneration after genotoxic stress

Area of Science:

• Hematology
• Molecular Biology
• Cancer Research

Background:

• Therapy failure in Acute Myeloid Leukemia (AML) is often due to leukemia cells escaping DNA damaging treatments.
• The specific molecular mechanisms driving this therapeutic resistance are not fully understood.

Purpose of the Study:

• To identify genes involved in Acute Myeloid Leukemia (AML) cell regeneration after DNA damage.
• To investigate the role of SMYD2 lysine methyltransferase (KMT) in AML therapy resistance.

Main Methods:

• Genome-wide shRNA screen to identify genes responsible for leukemia cell regeneration post-irradiation.
• Assessing the effect of SMYD2 knockdown on AML cell resistance to DNA damaging agents.
• Analyzing the expression of SET7/9 in response to SMYD2 downregulation.
• Evaluating the efficacy of SET7/9 inhibition using (R)-PFI2.

Main Results:

• SMYD2 knockdown conferred relative resistance to human AML cells against various DNA damaging agents.
• SMYD2 downregulation induced a transient quiescence state, correlating with resistance.
• Decreased SMYD2 expression led to increased SET7/9 expression, suggesting a compensatory mechanism.
• Pharmacological inhibition of SET7/9 preferentially inhibited the growth of AML cells with low SMYD2 levels.
• Lower SMYD2 expression in AML patients correlated with reduced therapy sensitivity and complete remission rates.

Conclusions:

• The interplay between SMYD2 and SET7/9 regulates the shift from growth to quiescence in leukemia cells, enhancing resistance to DNA damaging agents.
• Targeting SET7/9 is a potential therapeutic strategy for AML patients exhibiting low SMYD2 expression and therapy resistance.