Histone deacetylase inhibitors induce apoptosis in myeloid leukemia by suppressing autophagy

Abstract

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 anti-leukemic function of HDACis revealed their transcriptional and posttranslational 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 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.

Therapy reduction in patients with Down syndrome and myeloid leukemia: the international ML-DS 2006 trial

“…Recently, wee1 kinase inhibitors 35 or histone deacetylase inhibitors 36,37 have been identified as promising classes of drugs for the future treatment of ML-DS. Those drugs can be introduced to upcoming ML-DS protocols to substitute other less tolerated chemotherapeutic agents while increasing/maintaining overall efficacy.…”

miR-99a/100∼125b tricistrons regulate hematopoietic stem and progenitor cell homeostasis by shifting the balance between TGFβ and Wnt signaling

“…FL CD34 + HSPCs were purchased from Novogenic Laboratories. Culture conditions for maintenance, megakaryocytic, or megakaryocytic/erythroid in vitro differentiation of CD34 + HSPCs were described elsewhere (Klusmann et al 2010a;Kumar et al 2011;Emmrich et al 2012;Stankov et al 2014). Cell lines (CMK, K562, MV4:11, THP-1, and NB4) were purchased from the German National Resource Center for Biological Material (DSMZ) and maintained under recommended conditions.…”

Epigenetic alterations in acute myeloid leukemias

“…In particular, DNMT inhibitors, which inhibit DNMT1 and DNMT3, represent a class of drugs that have been used and approved for the treatment of patients affected by MDS [104]. Decitabine and 5-azacitidine, which irreversibly inhibit DNMTs by being incorporated into DNA during S phase, lead to the loss of CpG methylation, with consequent reactivation of silenced genes with a tumor suppressor role [105][106][107]. Another class of epigenetic drugs is represented by the HDAC inhibitors (HDACis), which have broad antitumor activity and low toxicity towards normal cells [102].…”