Crosstalk between hnRNP K and SET in ATRA‐induced differentiation in acute promyelocytic leukemia
Karina Stringhetta PadovaniRenata N. GotoLais Brigliadori FugioCristiana Bernadelli GarciaVani Maria AlvesMaría Sol BrassescoLewis Joel GreeneEduardo Magalhães RegoAndréia Machado Leopoldino
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Abstract:
HnRNP K protein is a heterogeneous nuclear ribonucleoprotein which has been proposed to be involved in the leukemogenesis of acute promyelocytic leukemia (APL), as well as in differentiation induced by all‐trans retinoic acid (ATRA). We previously demonstrated a connection between SET and hnRNP K function in head and neck squamous cell carcinoma (HNSCC) cells related to splicing processing. The objective of this study was to characterize the participation of hnRNP K and SET proteins in ATRA‐induced differentiation in APL. We observed higher (5‐ to 40‐fold) levels of hnRNP K and SET mRNA in APL patients at the diagnosis phase compared with induction and maintenance phases. hnRNP K knockdown using short‐hairpin RNA led to cell death in ATRA‐sensitive NB4 and resistant NB4‐R2 cells by apoptosis with SET cleavage. In addition, hnRNP K knockdown increased granulocytic differentiation in APL cells, mainly in NB4‐R2 with ATRA. hnRNP K knockdown had an effect similar to that of treatment with U0126 (an meiosis‐specific serine/threonine protein kinase/ERK inhibitor), mainly in NB4‐R2 cells. SET knockdown in APL cells revealed that apoptosis induction in cells with hnRNP K knockdown occurred by SET cleavage rather than by reduction in SET protein. Transplantation of NB4‐R2 cells into nude mice confirmed that arsenic trioxide (ATO) combined with U0126 has higher potential against tumor progression when compared to ATO. Therefore, hnRNP K/SET and ERK are potential therapeutic targets for both antineoplastic leukemia therapy and relapsed APL patients with ATRA resistance.Keywords:
Arsenic Trioxide
Promyelocytic leukemia protein
Tretinoin
Heterogeneous nuclear ribonucleoprotein
Acute promyelocytic leukemia (APL) is characterized by a specific chromosomal translocation, t(15;17)(q22;q21), which leads to a promyelocytic leukemia (PML) - retinoic acid receptor α (RARα) fusio...
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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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Acute promyelocytic leukemia (APL) is a subtype of acute myeloid leukemia (AML) characterized by the reciprocal translocation of t(15;17) (q22;q21) encoding the promyelocytic leukemia–retinoic acid...
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Mechanistic effects of arsenic trioxide on acute promyelocytic leukemia and other types of leukemias
Abstract Acute promyelocytic leukemia (APL), a subtype of acute myeloid leukemia characterized with a translocation between promyelocytic leukemia gene (PML) on chromosome 15 and retinoic acid receptor alpha gene (RARα) on chromosome 17. Transcription of this fusion gene results in PML/RARα fusion protein blocking expression of critical genes involved in differentiation of myeloid cells through interaction with RAR element. PML/RARα fusion protein prevents normal function of PML and RARα as well as inhibiting apoptosis. Arsenic trioxide (ATO) is an important agent for the treatment of relapsed and newly diagnosed APL. ATO induces apoptosis, autophagy, and partial cellular differentiation as well as inhibiting cell growth and angiogenesis. Recognition of signaling pathways and molecular mechanisms induced by ATO can be effective for discovering novel treatment strategies to target leukemia cells. Also, it can be developed for the treatment of a variety of cancer cells. This review provides a perspective on anticancerous effects of ATO on APL and leukemia cells.
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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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