Evolving Role of Arsenic Trioxide in Acute Promyelocytic Leukemia

Abstract Role of stromal microenvironment in drug resistance has been extensively reported for several cancers. We have demonstrated earlier that there is significant micro-environment mediated drug resistance (EM-DR) to arsenic trioxide (ATO) in acute promyelocytic leukemia (APL) and that this was predominantly driven by upregulation of the NF-ⱪB pathway in the malignant cell. In our current study we have probed the molecular mechanism of ATO resistance in further detail. The role of microRNA (miRNA) in mediating this cross talk, if any, has not been reported on. We undertook a study to evaluate the potential role played by miRNA in EM-DR to ATO in APL. Using NGS based small RNA sequencing we identified two miRNA's that were differentially regulated in NB4 cells upon co-culture with HS-5 stromal cells (FDR corrected p values < 0.05). The two miRNAs were hsa-miR-23a-5p (downregulated) and hsa-miR-125a-3p (upregulated)](Fig 1a). These miRNAs have also been previously reported to be involved in NF-kB regulation, specifically miR125a-3p has been reported to be involved in activation of the NF-kB pathway and miR-23a- 5p can be repressed by the same pathway. These results were consistent with our earlier reported observations that NF-kB pathway is dysregulated and enhances drug resistance to ATO. We also observed miR-23a-5p mimics were able to restore the sensitivity of NB4 cells to ATO even in the presence of stromal cells (Fig 1b). Consistent with the above small RNA sequencing and our previously reported microarray data, using quantitative proteomics approach we have identified that both NFkB signaling and metallothionein 2A (MT-2A) levels are upregulated in leukemic cells upon stromal co-culture. MT 2A is a known target for hsa-mir-23a-5p. MT's are known to sequester heavy metals such as arsenic and could potentially reduce their cytotoxic effect. The role of metallothionein in ATO resistance in APL and possibly other leukemia's needs further evaluation. This data along with that reported earlier by us illustrates multiple levels of regulation of the NF-kB pathway and resistance to ATO by stromal cell co-culture. Disclosures No relevant conflicts of interest to declare.

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Acute promyelocytic leukemia: evolving therapeutic strategies

Blood ◽

10.1182/blood.v99.3.759 ◽

2002 ◽

Vol 99 (3) ◽

pp. 759-767 ◽

Cited By ~ 279

Author(s):

Martin S. Tallman ◽

Chadi Nabhan ◽

James H. Feusner ◽

Jacob M. Rowe

Keyword(s):

Arsenic Trioxide ◽

Acute Promyelocytic Leukemia ◽

Remission Rate ◽

Therapeutic Strategies ◽

Promyelocytic Leukemia ◽

Leukemic Cells ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid ◽

Life Threatening

Abstract Acute promyelocytic leukemia (APL) is now the most curable subtype of acute myeloid leukemia in adults. All-trans retinoic acid (ATRA), which induces differentiation of the leukemic cells into mature granulocytes, represents the important advance. The incorporation of ATRA in induction results in a high complete remission rate, leads to rapid resolution of the characteristic life-threatening coagulopathy, and, most importantly, decreases the relapse rate compared with treatment with chemotherapy alone. However, ATRA is associated with unique toxicities not observed with conventional cytotoxic chemotherapy. A number of clinical trials have been performed to define the optimal role of ATRA in the treatment of patients. The therapeutic strategies have rapidly evolved as a result of both single institution and large cooperative group trials. Arsenic trioxide and stem cell transplantation are effective treatments for patients with APL who relapse after or are refractory to ATRA-based therapy. As experience with ATRA and arsenic trioxide in patients with APL accumulates, a number of important questions arise that need to be addressed.

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