Deregulation of apoptosis in acute myeloid leukemia

Abstract

Apoptosis, or programmed cell death, is central to the development and homeostasis of the hematopoietic system. Dysregulation of apoptosis plays an important role in the development of a variety of human pathologies, including cancer, autoimmune diseases and neurodegenerative disorders. Studies carried out in the last years have shown that leukemia cells invariably have abnormalities in one or more apoptotic pathways, determining a survival advantage of these cells over their normal counterpart. Furthermore, abnormalities in the apoptotic response also play a role in the development of drug resistance by leukemic cells. The identification of the different components of the apoptotic pathways has enabled the detection of various biochemical defects present in leukemic cells compared to their normal counterparts. These defects contribute to the survival advantage of the leukemic clone over the normal hematopoietic cells and are also frequently associated with a low rate of response to standard chemotherapy treatment and with poor survival. Furthermore, these findings have lead to the identification of many potential apoptotic targets for the development of new drugs targeting anti-apoptotic molecules abnormally expressed or regulated in leukemic cells. Many of these drugs restore the sensitivity of leukemic cells to apoptotic stimuli and some of them are under investigation at a clinical level.

Overexpression of Bcl2 protein predicts chemoresistance in acute myeloid leukemia: Its correlation with FLT3

“…Several lines of evidence indicate that leukemic cells undergo apoptosis in response to chemotherapy, suggesting an association between therapy-induced apoptosis and therapeutic efficacy in AML [5]. Abnormalities in the apoptotic pathway give survival advantage to the leukemic cells and thereby play major role in development of drug resistance [4].…”

“…Apoptosis plays key role in the control of tissue homeostasis, such as rapidly renewing hematopoietic tissue [4] and deregulation of apoptosis may give rise to neoplastic transformation. Several lines of evidence indicate that leukemic cells undergo apoptosis in response to chemotherapy, suggesting an association between therapy-induced apoptosis and therapeutic efficacy in AML [5].…”

Loss of DNAM-1 ligand expression by acute myeloid leukemia cells renders them resistant to NK cell killing

“…35 Finally, intrinsic resistance to apoptosis may play a role in resistance to NKcell-mediated killing, downstream of granule entry. 36 Here, we demonstrate that poor NK cell function against AML cells originates through an early conjugation defect, which is deregulated through aberrant expression of DNAM-1 ligands. This resulted in a failure of NK cells to degranulate and kill the AML tumor cells.…”

The Many Virtues of tRNA-derived Stress-induced RNAs (tiRNAs): Discovering Novel Mechanisms of Stress Response and Effect on Human Health

“…Both 5Ј-tiRNAs and 3Ј-tiRNAs exhibited cyt c binding. Deeper understanding of these tiRNA-cyt c complexes will provide insights helpful for designing RNA-based therapeutics for diseases that involve deregulation of the apoptotic pathway such as various cancers and neurodegenerative diseases (29,30).…”

“…Both 5Ј-tiRNAs and 3Ј-tiRNAs exhibited cyt c binding. Deeper understanding of these tiRNA-cyt c complexes will provide insights helpful for designing RNA-based therapeutics for diseases that involve deregulation of the apoptotic pathway such as various cancers and neurodegenerative diseases (29,30).In addition to stress response pathways, tiRNAs are also speculated to participate in the cellular RNAi pathway by associating with the Argonaute (Ago) proteins and other proteins involved in the silencing pathway (7). Increased tRNA cleavage during heat shock in flies lacking the Dnmt2 modification enzyme has been shown to interfere with the siRNA pathway.…”