All-trans retinoic acid and cyclic adenosine monophosphate cooperate in the expression of leukocyte alkaline phosphatase in acute promyelocytic leukemia cells

Treatment of acute promyelocytic leukemia (APL) blasts with cyclic adenosine monophosphate (cAMP) analogs, in combination with all-trans retinoic acid (ATRA), results in the upregulation of the expression of leukocyte alkaline phosphatase (LAP), a marker for the differentiation of the granulocyte. The synergistic interaction between the cyclic nucleotide analogs and the retinoid is not unique to APL cells, as it is observed also in the peripheral granulocytes of chronic myelogenous leukemia (CML) patients. The molecular mechanisms underlying LAP induction were studied in NB4, an immortalized APL cell line. Induction of LAP enzymatic activity is dependent on the time of exposure and on the concentrations of dibutyryl-cAMP or 8-bromo-cAMP and ATRA, two factors that influence the kinetics of appearance of detectable levels of the enzyme. Augmentation of LAP levels by ATRA and cAMP is the result of both transcriptional and early posttranscriptional events and requires de novo protein synthesis. LAP induction correlates with augmentation in the levels of the type I catalytic subunit of cAMP-dependent protein kinase transcript and with granulocytic differentiation. The transcriptional component of the process leading to increased LAP gene expression was reproduced in its main features by transient transfection experiments performed in COS-7 cells using the normal retinoic acid receptor type alpha (RAR-alpha) or the APL-specific aberrant form (PML-RAR) and the upstream promoter of the liver/bone/kidney (L/B/K)-type alkaline phosphatase gene. The promoter is upregulated by treatment with ATRA, and this upregulation is further increased by cAMP analogs.

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Stat1 Is Induced and Activated by All-Trans Retinoic Acid in Acute Promyelocytic Leukemia Cells

Blood ◽

10.1182/blood.v89.3.1001 ◽

1997 ◽

Vol 89 (3) ◽

pp. 1001-1012 ◽

Cited By ~ 89

Author(s):

Maurizio Gianni ◽

Mineko Terao ◽

Ida Fortino ◽

Marco LiCalzi ◽

Vincenzo Viggiano ◽

...

Keyword(s):

Retinoic Acid ◽

Acute Promyelocytic Leukemia ◽

Intracellular Signaling ◽

Retinoic Acid Receptor ◽

Leukemia Cell ◽

Promyelocytic Leukemia ◽

Myelogenous Leukemia ◽

Oligoadenylate Synthetase ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid

Abstract Treatment of freshly isolated acute promyelocytic leukemia (APL) cells and the myelogenous leukemia cell lines, NB4, HL-60, and U937, with all-trans retinoic acid (ATRA) results in a remarkable elevation in the amounts of Stat1α and Stat2 proteins. Stat1α protein levels are augmented by ATRA as a consequence of elevated amounts of the corresponding transcripts. The retinoid increases the levels of nuclear complexes that are capable of binding to interferon (IFN)-regulated consensus sequences and contain Stat1 and/or Stat2 proteins, and causes a rapid and long-lasting elevation in Stat1α tyrosine phosphorylation. Transient transfection experiments show that ATRA enhances the transactivating properties of Stat1α observed on an appropriate reporter gene, in the presence of the RARα retinoic acid receptor, but not in the presence of the PML-RAR protein. Treatment of NB4 cells with ATRA is associated with a remarkable upregulation of the two IFN-responsive genes IFN-responsive factor 1 and 2′-5′ oligoadenylate synthetase, as well as with an augmentation in the levels of IFNα secretion. Our data show that ATRA is capable of modulating the amounts and the state of activation of some of the components of the IFN intracellular signaling pathways. They also suggest that the retinoid can bypass IFN/IFN-receptor interactions and induce the expression of IFN-regulated genes.

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Faculty Opinions recommendation of Internal tandem duplication of the FLT3 gene confers poor overall survival in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and anthracycline-based chemotherapy: an International Consortium on Acute Promyelocytic Leukemia study.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.727821468.793534675 ◽

2017 ◽

Author(s):

Wee Joo Chng

Keyword(s):

Overall Survival ◽

Retinoic Acid ◽

Acute Promyelocytic Leukemia ◽

Tandem Duplication ◽

Promyelocytic Leukemia ◽

Poor Overall Survival ◽

Internal Tandem Duplication ◽

International Consortium ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid

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Hypercalcemia associated with the interaction between all trans retinoic acid and posaconazole in an acute promyelocytic leukemia case

Journal of Oncology Pharmacy Practice ◽

10.1177/10781552211007889 ◽

2021 ◽

pp. 107815522110078

Author(s):

Hacer Berna Afacan Ozturk ◽

Murat Albayrak ◽

Senem Maral ◽

Merih Reis Aras ◽

Fatma Yilmaz ◽

...

Keyword(s):

Retinoic Acid ◽

Acute Promyelocytic Leukemia ◽

Serum Calcium ◽

Promyelocytic Leukemia ◽

Cytochrome P450 Enzymes ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid ◽

Normal Ranges ◽

Rare Side Effect ◽

High Level

Introduction All-trans retinoic acid (ATRA) is a physiological metabolite of vitamin A and it is used for the treatment of acute promyelocytic leukemia (APL). Hypercalcemia is a rare side effect of ATRA and it may be potentiated after interaction of ATRA with azole group antifungals. Herein, we have reported an APL case with hypercalcemia that is caused by the interaction of ATRA and posaconazole. Case Report A 49-year-old female patient was diagnosed as APL after the examinations performed upon the detection of pancytopenia when she had presented with the complaints of widespread bruising and fever. After the initiation of posaconazole and ATRA, her serum calcium levels begin to increase (10.3 to 11.1mg/dl). Her vitamin D level was 21.9 ng/ml and PTH 17.8 pg/ml, both were in the normal ranges. The Drug Interaction Probability Scale score of our case was calculated as 6, indicating that the probable adverse drug reaction. Therefore, the high level of serum calcium was attributed to the interaction between ATRA and posaconazole. Management & Outcome Although hypercalcemia with ATRA and other antifungal agents have been previously reported in the literature, this is the first report of hypercalcemia with the concomitant use of ATRA and posaconazole. Discussion This case highlights the importance of monitoring ATRA’s side effects when it is used in combination with drugs inhibiting the cytochrome P450 enzymes. In conclusion, the concomitant use of posaconazole and ATRA may lead to hypercalcemia and serum calcium levels return to normal ranges with the discontinuation of these drugs.

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