Overcoming treatment resistance in acute promyelocytic leukemia and beyond

  title={Overcoming treatment resistance in acute promyelocytic leukemia and beyond},
  author={T. Fung and C. So},
  pages={1128 - 1129}
From the introduction of all-trans retinoic acid (ATRA) to the recent development of arsenic trioxide (ATO) treatment, acute promyelocytic leukemia (APL) characterized by the presence of retinoic acid receptor alpha (RARA) fusion has been transformed from a highly fatal cancer to a highly curable disease. In spite of this unprecedented success, there are still a significant number of high-risk patients who fail to achieve a complete molecular remission or relapse and become resistant to the… Expand
Advances in precision epigenetic treatment for acute promyelocytic leukemia.
Despite an integral role of epigenetic factors in the development, pathogenesis, and emergence of drug resistance in APL, their therapeutic importance has not been fully explored clinically and many epigenetic drugs are in clinical trials for myeloid neoplasms different from APLs. Expand
Epigenetics in acute promyelocytic leukaemia pathogenesis and treatment response: A TRAnsition to targeted therapies
The molecular basis and the upcoming challenges of targeted therapies in APL are reviewed, and the recent advance in the understanding of epigenetics underlying ATRA response is discussed and their potential use to further improve treatment response and overcome resistance are discussed. Expand
New Strategies in Acute Promyelocytic Leukemia: Moving to an Entirely Oral, Chemotherapy-Free Upfront Management Approach
Data suggest that delays in initiation of ATRA upon suspecting APL continue to occur in the community and contribute to early mortality, and questions remain about the optimal place and schedule of arsenic in the therapeutic sequence and the role of the oral formulations. Expand
Reprogramming acute myeloid leukemia into sensitivity for retinoic-acid-driven differentiation.
It is hypothesized that reprogramming by inhibitors of epigenetic-modifying enzymes or by modulation of microRNA expression might sensitize non-APL AML cells for RA-based therapy, and searching for response biomarkers might reveal novel RA- based combination therapies with an efficient differentiation/apoptosis-inducing effect in non-APS AML patients. Expand
Varying responses of PML-RARA with different genetic mutations to arsenic trioxide.
It is demonstrated that either increasing the concentration of arsenic trioxide or combining it with ATRA could overcome the mutation-triggered arsenic resistance in vitro, and novel insight is provided into the functional difference of acquired mutations of PML-RARA both in vitro and in the clinical setting. Expand
Phenylarsine Oxide Can Induce the Arsenite-Resistance Mutant PML Protein Solubility Changes
Interestingly, PAO is found to have potential effect on induction of mutant PML-IV (A216V) protein solubility changes and degradation, but no appreciable effects were found following exposure to high concentrations of iAsIII, dimethylarsinous acid (DMAIII) and adriamycin (doxorubicin), even though they cause cell death. Expand
Retinoid receptor signaling and autophagy in acute promyelocytic leukemia.
Retinoid signaling in hematopoiesis, leukemogenesis, and APL treatment is discussed and autophagy is highlighted as a potential important regulator in anti-leukemic strategies. Expand
Synergistic activity of parthenolide and cytarabine in acute promyelocytic leukemia HL-60 cell line
Aim: Investigation of the influence of parthenolide (PTL) on cytarabine (Ara-C) action in an acute promyelocytic leukemia HL-60 cell line and the role of oxidative stress in its action. Methods:Expand
Evaluating frequency of PML-RARA mutations and conferring resistance to arsenic trioxide-based therapy in relapsed acute promyelocytic leukemia patients
This study demonstrated frequent mutations of PML-RARA and supported a clonal selection model in relation to APL relapse and ATO resistance and showed alternating clonal dominance over the course of treatment. Expand
HA117 endows HL60 cells with a stem-like signature by inhibiting the degradation of DNMT1 via its ability to down-regulate expression of the GGL domain of RGS6
It is demonstrated that ATRA induces multi-drug-resistant subpopulations of HL60 cells with a putative stem-like signature by up-regulating the expression of the new drug resistance-related gene segment HA117, and shows that HA117 potentially promotes the stem- like signature of the HL60/ATRA cell line by inhibiting by the ubiquitination and degradation of DNMT1 and by down-regulate theexpression of the GGL domain of RGS6. Expand