Cancer Control (Jul 2024)

Aberrant HIF1- α and SIX-1 Expression is Associated with Poor Prognosis in Acute Myeloid Leukemia Patients with Isocitrate Dehydrogenase 1 Mutations

  • Tariq Ali MS,
  • Rohma Usman MS,
  • Syed Alasar Shah MS,
  • Aamir Parvez MD,
  • Summayya Anwar MS,
  • Zahid Muneer PhD,
  • Muhammad Saeed PhD

DOI
https://doi.org/10.1177/10732748241271714
Journal volume & issue
Vol. 31

Abstract

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Background IDH1 mutations are common in many cancers, however, their role in promoting the Warburg effect remains elusive. This study elucidates the putative involvement of mutant-IDH1 in regulating hypoxia-inducible factor (HIF1-α) and Sine-Oculis Homeobox-1 (SIX-1) expression. Methodology Genetic screening was performed using the ARMS-PCR in acute myeloid leukemia (AML), brain, and breast cancer (BC) cohorts, while transcript expression was determined using qPCR. Further, a meta-analysis of risk factors associated with the R132 mutation was performed. Results Approximately 32% of AML and ∼60% of glioma cases were mutants, while no mutation was found in the BC cohort. ‘AA’ and TT’ were associated with higher disease risk (OR = 12.18 & 4.68) in AML and had significantly upregulated IDH1 expression. Moreover, downregulated HIF1-α and upregulated SIX-1 expression was also observed in these patients, suggesting that mutant-IDH1 may alter glucose metabolism. Perturbed IDH1 and HIF-α levels exhibited poor prognosis in univariate and multivariate analysis, while age and gender were found to be contributory factors as well. Based on the ROC model, these had a good potential to be used as prognostic markers. A significant variation in frequencies of R132 mutations in AML among different populations was observed. Cytogenesis ( R 2 = 12.2%), NMP1 mutation status ( R 2 = 18.5%), and ethnic contributions ( R 2 = 73.21%) were critical moderators underlying these mutations. Women had a higher risk of R132 mutation (HR = 1.3, P < 0.04). The pooled prevalence was calculated to be 0.29 (95% CI 0.26-0.33, P < 0.01), indicating that IDH1 mutations are a significant prognostic factor in AML. Conclusion IDH1 and HIF1-α profiles are linked to poor survival and prognosis, while high SIX-1 expression in IDH1 mutants suggests a role in leukemic transformation and therapy response in AML.