The creatine kinase pathway is a therapeutic target for EVI1 positive AML

Ectopic Viral Integration site 1 (EVI1), also called MECOM, is a proto-oncogene that is located on chromosomal band 3q26.2. EVI1 is expressed in 5­­–10% of Acute Myeloid Leukemia (AML) patients.  Aberrant expression of EVI1 in AML patients is characterized with very poor survival outcomes in this subgroup of patients.¹ Furthermore, abnormal expression of EVI1 promotes the development and progression of high-risk AML for which current treatment strategies are inadequate.²

Several studies have revealed that cancer cells have a strong dependency on cellular metabolism, thus metabolic pathways are an attractive therapeutic target.³ Moreover, abnormal expression of genes encoding metabolic enzymes or transcription factors such as EVI1 can lead to deregulation of metabolic pathways.²

Using genomic and metabolic screening, Nina Fenouille et al. from the Koch Institute for Integrative Cancer Research at Massachusetts Institute of Technology, Massachusetts, investigated a metabolic target for EVI1 positive AML. The results of the study was published ahead of print in Nature Medicine on 13^th February 2017.² 

The key results of the study were:

• Using short hairpin RNAs (shRNAs), Mitochondrial Creatine Kinase 1 (CKMT1) was identified as a target in EVI1 positive AML
• CKMT1 protein expression and activity was elevated in EVI1 expressing human AML cell lines
• Viability of EVI1 expressing cell lines with high levels of CKMT1 decreased upon treatment with cyclocreatine (an inhibitor of the creatine biosynthesis pathway)
• Depletion of CKMT1 in EVI1 expressing human AML cells led to cell growth inhibition
• RUNX1 repressed CKMT1 expression by binding to its promoter
• EVI1 repressed RUNX1 expression, thus leading to an elevated level of CKMT1
• Decreased levels of phosphocreatine and blocked production of ATP was observed upon CKMT1-directed shRNAs or treatment with cyclocreatine in EVI1 expressing human AML cells
• Addition of exogenous phosphocreatine to EVI1 expressing human AML cells increased viability and restored normal mitochondrial function
• In mice injected with human EVI1 positive cells, inhibition of the CKMT1 dependent pathway prolonged survival and had attenuated disease compared to control mice, which demonstrated aggressive AML and had a short latency

CKMT1 was identified as a druggable liability in EVI-1 positive AML. Hence, targeting CKMT1 may be an effective therapeutic strategy for EVI1 positive AML patients. In conclusion, Fenouille et al. suggested that their study supports a potential therapeutic avenue for targeting the creatine kinase pathway in EVI1 positive AML. The results of this study were presented that the American Society of Hematology meeting in December 2016.

Abstract

Expression of the MECOM (also known as EVI1) proto-oncogene is deregulated by chromosomal translocations in some cases of acute myeloid leukemia (AML) and is associated with poor clinical outcome. Here, through transcriptomic and metabolomic profiling of hematopoietic cells, we reveal that EVI1 overexpression alters cellular metabolism. A screen using pooled short hairpin RNAs (shRNAs) identified the ATP-buffering, mitochondrial creatine kinase CKMT1 as necessary for survival of EVI1-expressing cells in subjects with EVI1-positive AML. EVI1 promotes CKMT1 expression by repressing the myeloid differentiation regulator RUNX1. Suppression of arginine–creatine metabolism by CKMT1-directed shRNAs or by the small molecule cyclocreatine selectively decreased the viability, promoted the cell cycle arrest and apoptosis of human EVI1-positive cell lines, and prolonged survival in both orthotopic xenograft models and mouse models of primary AML. CKMT1 inhibition altered mitochondrial respiration and ATP production, an effect that was abrogated by phosphocreatine-mediated reactivation of the arginine–creatine pathway. Targeting CKMT1 is thus a promising therapeutic strategy for this EVI1-driven AML subtype that is highly resistant to current treatment regimens.