On Tuesday 4th April, at the 107th American Association for Cancer Research (AACR) annual meeting in Washington, DC, USA, there was an enthralling poster session on “Mitosis, Telomeres, and Proliferation”. During this session, a poster (3472/22) titled “Separase overexpression defines a new subset of acute myeloma leukemia patients characterized by high CD34 and MYC levels” by Giorgia Simonetti from the University of Bologna, Bologna, Italy, and colleagues was on display.
Separase is encoded by the ESPL1 gene, and is a cohesin regulatory factor. The role of Separase in Acute Myeloid Leukemia (AML) is not yet elucidated. Simonetti et al. aimed to investigate the expression of Separase in AML patients. The genomic landscape of 405 and 78 AML cases were profiled by SNP array and whole exome sequencing, respectively.
The key results were:
- One patient (1/78) exhibited a nonsynonymous mutation in ESPL1 (1.3%), which was predicted to alter the protein function
- ESPL1 copy number gain was observed in 1.2% (5/405); hyperdiploid AML (2), trisomy 12 (1), and a short gain at 12q (2)
- Using immunohistochemistry to analyze bone marrow AML samples (n = 44), Separase was overexpressed in 29 samples (66%, Separase-high), compared to biopsies in the remaining 15 samples (Separase-low)
- Median age of patients with high and low expression of Separase; 64 vs 57 years, P = 0.01
- Patients with high Separase had a 17-fold upregulation in CD34 compared to patients with low expression of Separase, P = 0.004
- NPM1, FLT3, cohesion gene lesions, frequent mutations in genes involved in protein post-translational modification, and ubiquitination mutations co-occurred with high expression of Separase
- RAS signaling pathway was enriched in patients with low Separase expression
- Reduced expression of HOXA/B family genes, the DNA damage repair gene ATM, the p53 regulator MDM2, and forced expression of the cell cycle markers, independently of chromosome 8 gain, were observed in AML with high expression of Separase
The authors concluded by stating that “Separase overexpression is a common feature and defines a new subset of AML cases with a distinct gene expression profile”. Moreover, “genomic lesions targeting ESPL1 are a rare event in AML”.