Assistant Professor at Department of Molecular Biology and Genetics Abdullah Gül University (AGU)
Çağrılı Konuşma Konusu: Autophagy repression: A novel anti-leukemic function of histone deacytelase inhibitors
Histone deacetylase (HDAC) inhibitors (HDACis) are well-characterized anti-cancer agents with promising results in clinical trials. However, mechanistically little is known regarding their selectivity in killing malignant cells while sparing normal cells. Gene expression-based chemical genomics identified HDACis as being particularly potent against Down syndrome-associated myeloid leukemia (DS-AMKL) blasts. Investigating the antileukemic function of HDACis revealed their transcriptional and post-translational regulation of key autophagic proteins, including ATG7. This leads to suppression of autophagy, a lysosomal degradation process that can protect cells against damaged or unnecessary organelles and protein aggregates. DS-AMKL cells exhibit low baseline autophagy due to mammalian target of rapamycin (mTOR) activation. Consequently, HDAC inhibition repressed autophagy below a critical threshold, which resulted in accumulation of mitochondria, production of reactive oxygen species, DNA damage and apoptosis. Those HDACi-mediated effects could be reverted upon autophagy activation or aggravated upon further pharmacological or genetic inhibition. Our findings were further extended to other major acute myeloid leukemia subgroups with low basal level autophagy. The constitutive suppression of autophagy due to mTOR activation represents an inherent difference between cancer and normal cells. Thus, via autophagy suppression, HDACis deprive cells of an essential pro-survival mechanism, which translates into an attractive strategy to specifically target cancer cells.
Dr. Mona El Khatib is currently an Assistant Professor at the Department of Molecular Biology and Genetics, Faculty of life and Natural Sciences at Abdullah Gul University in Kayseri, Turkey. She was a Postdoctoral researcher at Hannover Medical School, Germany from 2012 until 2014. Her research focused on establishing a humanized mouse model in order to examine the effects of selective drugs that target deregulated key pathways in acute myeloid leukemia where her work was published in Oncogene and Leukemia. Dr. El Khatib obtained her PhD in 2012 from Hannover Medical School. She was awarded Summa cum laude (Excellent Grade) for the PhD thesis entitled: “Analysis of Sonic Hedgehog and Notch Signaling Pathways in the Carcinogenesis of Cholangiocarcinomas”. Her work was published in many journals among which are Cancer Cell and Hepatology and awarded “Best Poster Prize” at Falk Symposium, Germany. During her PhD and Postdoc, Dr. El Khatib mentored and supervised PhD and medical students. She did her Masters and Bachelors in Biology at the American University of Beirut, Lebanon.