Evaluating frequency of PML-RARA mutations and conferring resistance to arsenic trioxide-based therapy in relapsed acute promyelocytic leukemia patients
Yinjun LouYafang MaJianai SunXiujin YeHanzhang PanYungui WangWenbin QianHaitao MengWenyuan MaiJingsong HeHongyan TongJie Jin
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Arsenic Trioxide
Hematology
Sanger sequencing
Tretinoin
Acute promyelocytic leukemia (APL), is a homogeneous subgroup of acute myelogenous leukemias characterized by phenotypic and genetic markers. APL is associated with a reciprocal chromosomal translocation t(15,17) which has been shown to disrupt the retinoic acid receptor alpha (RAR alpha) gene. As a result, a portion of the RAR alpha gene becomes fused with a chromosome 15 locus termed PML (promyelocytic myeloid leukemia) from which chimeric PML/RAR alpha fusion mRNAs are expressed. The presence of these fusion transcripts in APL patients strongly support the hypothesis that both the t(15;17), and thus PML/RAR alpha, play a crucial role in the leukemogenesis of this disease. APL cells are specifically responsive to all-trans retinoic acid (ATRA) and this characteristic has allowed the first differentiation therapy with retinoic acid. However, failure or partial responses are observed and, though this has most frequently been reported in patients at second or third relapse. The molecular basis of the absence of ATRA response in these patients has not been determined.
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Abstract The use of arsenic trioxide (As 2 O 3 , ATO) combined with all‐trans retinoic acid (ATRA) has recently been reported to induce remission in patients with acute promyelocytic leukemia (APL). However, its efficiency remains inconclusive mainly due to the small number of the available cases. In this study, therefore, we present a clinical study using a combination of ATO with low‐dose ATRA (LD‐ATRA) to treat 108 APL patients (80 newly diagnosed patients, 28 relapsed patients). Therapeutic outcomes using the ATO/LD‐ATRA approach were compared with those of APL patients treated either with ATO alone (65 patients) or ATRA alone (51 patients). The results showed that the ATO/LD‐ATRA approach provided significantly better therapeutic outcomes as compared to either ATO or ATRA alone, as evidenced by lower mortality, a higher CR rate and a reduced period to CR. In addition, the toxic side‐effects have been no worse with the combined ATO/LD‐ATRA treatment than with either ATO or ATRO alone and in some cases have been reduced. These data suggest that the ATO/LD‐ATRA regimen is superior to either regimen given alone to patients with APL. Copyright © 2004 John Wiley & Sons, Ltd.
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Although arsenic trioxide (ATO) treatment has transformed acute promyelocytic leukemia (APL) from the most fatal to the most curable hematological cancer, many high-risk APL patients who fail to achieve a complete molecular remission or relapse become resistant to ATO. Herein, we report that 7-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptanamide (CUDC-101) exhibits specific anticancer effects on APL and ATO-resistant APL in vitro and in vivo , while showing negligible cytotoxic effect on the noncancerous cells including normal CD34 + cells and bone marrow mesenchymal stem cells from APL patients. Further mechanistic studies show that CUDC-101 triggers caspase-dependent degradation of the promyelocytic leukemia-retinoic acid receptor alpha fusion protein. As a result, APL and ATO-resistant APL cells undergo apoptosis upon CUDC-101 treatment and this apoptosis-inducing effect is even stronger than that of ATO. Finally, using a xenograft mouse model, we demonstrated that CUDC-101 significantly represses leukemia development in vivo . In conclusion, these results suggested that CUDC-101 can serve as a potential candidate drug for APL, particularly for ATO-resistant APL.
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To summarize limitations involved in arsenic trioxide therapeutic effects in acute promyelocytic leukemia, because current studies show that some individuals of acute promyelocytic leukemia have relatively poor outcomes during treatment with arsenic trioxide.Most relevant articles were included in the PubMed database between 2000 and 2013 with the keywords "acute promyelocytic leukemia," "arsenic trioxide," "thiol" or "methylation." In addition, a few older articles were also reviewed.Data and articles related to arsenic trioxide effect in acute promyelocytic leukemia treatment were selected and reviewed. We developed an overview of limitations associated with arsenic trioxide therapeutic effect.This review focuses on the researches about the arsenic trioxide therapeutic effect in acute promyelocytic leukemia and summarizes three mainly limitations which can influence the arsenic trioxide therapeutic effect to different degrees. First, with the combination of arsenic and glutathione the therapeutic effect and cytotoxicity decrease when glutathione concentration increases; second, arsenic methylation, stable arsenic methylation products weaken the apoptosis effect of arsenic trioxide in leukemia cells; third, gene mutations affect the sensitivity of tumor cells to arsenic trioxide and increase the resistance of leukemia cells to arsenic trioxide.The chief limitations are listed in the review. If we can exclude all of them, we can obtain a better therapeutic effect of arsenic trioxide in patients with acute promyelocytic leukemia.
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All-trans retinoic acid can induce complete remissions in patients with acute promyelocytic leukemia. The balanced chromosomal translocation t(15;17)(q22;q12-21) of this malignancy is now known to involve the nuclear retinoic acid receptor-alpha (RAR-alpha) on the long arm of chromosome 17 and a novel gene on the long arm of chromosome 15, designated PML (previously called myl). A unique fusion mRNA, PML/RAR-alpha, is produced. Paradoxically, this rearrangement of RAR-alpha results in clinical sensitivity to retinoic acid. Despite its efficacy, retinoic acid therapy has side effect, including a syndrome of hyperleukocytosis and respiratory distress in some patients. Remissions induced and maintained by continuous all-trans-retinoic treatment are not durable in most of these patients. Retinoic acid therapy for acute promyelocytic leukemia represents a unique example where a molecular defect may be involved both in the pathogenesis and treatment of a malignancy.
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Objective:To observe the arsenic trioxide (As2O3) combined with alltransretinoic acid (ATRA) treatment of acute promyelocytic leukemia (APL) of the efficacy and toxicity.Methods: 21 patients with acute promyelocytic leukemia (APL) patients with doubleAs2O3 combined ATRA induction therapy,patients with high white blood cell with a single chemotherapy drug third year plus tipshirt ester base (H) or daunorubicin (DNR).Results:In 21 patients,19 cases of complete remission,complete remission (CR) rate of 90.47%;1 patient died of intracranial hemorrhage.Conclusion:arsenic trioxide combined with alltrans retinoic acid treatment of acute promyelocytic leukemia precise and well tolerated in patients.
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Chinese clinical investigators in 1986 demonstrated the therapeutic potential of tretinoin and in 1992 that of arsenic trioxide in the treatment of acute promyelocytic leukaemia. These observations have been confirmed in European and American centres. In acute promyelocytic leukaemia there is an abnormal receptor for retinoids, designated PML/RAR-alpha. This receptor binds retinoids inadequately so that extra retinoids (in the form of tretinoin) are required to restart the normal cellular maturation, after which the promyelocytes can mature into granulocytes. Arsenic trioxide has a different mode of action, possibly related to its effects on sulfhydryl-rich proteins, resulting in dysplastic leukaemic promyelocytes, ending up in apoptotic cell death. Since 1990 tretinoin has been included worldwide in the treatment of acute promyelocytic leukaemia. The use of arsenic trioxide has not yet been included in treatment protocols for promyelocytic leukaemia in western medicine.
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