herg1bExpression as a Potential Specific Marker in Pediatric Acute Myeloid Leukemia Patients with HERG 897K/K Genotype

Abstract

Human ether-a-go-go related gene (herg) encoding HERG K(+) channel has been demonstrated in many previous studies with its association to cell cycle progression and growth in tumor cells. The upregulated expression of HERG K+ channels was determined in different tumor types. Furthermore, not only full-length transcript herg1 but also a truncated isoform herg1b was shown to be expressed in cancer cells. In this study, the expression levels of herg1 and herg1b and the impact of K897T mutation on their expressions were investigated in pediatric acute myeloid leukemia (pAML). Expression levels of herg1 and herg1b isoforms were analyzed by quantitative real time polymerase chain reaction (PCR) in pAML patients together with healthy donors, and their expressions were confirmed by western blotting. The 2690 A>C nucleotide variation in KCNH2 gene corresponding to K897T amino acid change was analyzed by PCR followed by restriction enzyme digestion. herg1b overexpression was observed in tumor cells compared to healthy controls (P = .0024). However, herg1 expression was higher in healthy control cells than tumor cells (P = .001). The prevalence of polymorphic allele 897T was 26% in our patient group and 897T carriers showed increased herg1b expression compared to wild-type allele carriers. Our results demonstrate the presence of the increased levels of herg1b expression in pAML. In addition, we report for the first time that, pAML subgroup with HERG 897K/K genotype compared to 897K/T and T/T genotypes express increased levels of herg1b. In conclusion, HERG 897K/K genotype with increased level of herg1b expression might well be a prognostic marker for pAML.

hERG K+ Channels Promote Survival of Irradiated Leukemia Cells

“…Finally, the truncated, N-deleted splice variant hERG1b is reportedly up-regulated during the S phase of cell cycle, while the full-length hERG1a protein increases its expression on the plasma membrane during the G1 phase (Crociani et al, 2003). Consequently, proliferating tumor cells should exhibit higher hERG1b/1a expression ratios than terminally differentiated cardiomyocytes (Larsen et al, 2008) as has indeed been reported for some tumors (Erdem et al, 2015). Inhibitor selectivity for variant 1b over 1a (Gasparoli et al, 2015) might be a further strategy to develop tumor-specific hERG1 blockers.…”

Repurposing old drugs in oncology: Opportunities with clinical and regulatory challenges ahead

“…Wang et al later reported that the hERG channel is a regulator of tumour cell proliferation and apoptosis. This channel is also overexpressed in leukaemia cells, regulating their proliferation . Using immunohistochemistry and real‐time PCR techniques, Liang et al have shown that the expression rate of hERG in laryngeal carcinomatous tissue was far higher than in mucosa adjacent to the cancer.…”

Peptides and small molecules blocking the CXCR4/CXCL12 axis overcome bone marrow‑induced chemoresistance in acute leukemias

“…hERG1 is a voltage-dependent potassium channel, the functional relevance of which in human leukemia has been repeatedly proven (7,(9)(10)(11). Furthermore, the alternative transcript of the hERG1 gene, hERG1B, is an independent prognostic factor of a high risk of relapse in pediatric T-ALL (12).…”