scholarly journals All‐ trans retinoic acid (ATRA)‐induced TFEB expression is required for myeloid differentiation in acute promyelocytic leukemia (APL)

2020 ◽  
Vol 104 (3) ◽  
pp. 236-250 ◽  
Author(s):  
Nina Orfali ◽  
Tracey R. O'Donovan ◽  
Mary R. Cahill ◽  
Dalyia Benjamin ◽  
David M. Nanus ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Acute Promyelocytic Leukemia ◽  
Promyelocytic Leukemia ◽  
Myeloid Differentiation ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid

Restoration of CCAAT Enhancer Binding Protein Alpha P42 Overcomes Myeloid Differentiation Block and All-Trans Retinoic Acid Resistance in Human Acute Promyelocytic Leukemia NB4-R1 Cells

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1238-1238 ◽  
Author(s):  
Limengmeng Wang ◽  
Haowen Xiao ◽  
Xing Zhang ◽  
Weichao Liao ◽  
Shan Fu ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Acute Promyelocytic Leukemia ◽  
Morphological Changes ◽  
Promyelocytic Leukemia ◽  
Mtor Pathway ◽  
Myeloid Differentiation ◽  
Differentiation Therapy ◽  
Cd11b Expression ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid

Abstract All-trans retinoic acid (ATRA) is one of the first line agents in differentiation therapy for acute promyelocytic leukemia (APL). However, drug resistance becomes a major problem which influences the efficacy of ATRA. Mechanisms of ATRA resistance are ugly needed to be identified. Here we found that expression of C/EBPα, an important transcription factor for myeloid differentiation, was significantly suppressed in ATRA resistant APL cell line NB4-R1 compared with ATRA sensitive NB4 cells. Moreover, two forms of C/EBPα were unequally suppressed in NB4-R1 cells. Suppression of the full-length form P42 was more pronounced than the truncated form P30. Inhibition of PI3K/Akt/mTOR pathway was also observed in NB4-R1 cells. Meanwhile, C/EBPα expression was reduced by PI3K inhibitor LY294002 and mTOR inhibitor RAD001 in NB4 cell, suggesting that inactivation of the PI3K/Akt/mTOR pathway was responsible for C/EBPα suppression in APL cells. Then, we restored C/EBPα P42 and P30 by lentivirus vectors in NB4-R1 cells respectively, and found C/EBPα P42, but not P30, could increase CD11b, CD14, G-CSFR and GM-CSFR expression, which indicated the occurrence myeloid differentiation. Moreover, further upregulating of CD11b expression and differential morphological changes were found in NB4-R1 cells with restored C/EBPα P42 after ATRA treatment. However, CD11b expression and differential morphological changes could not be induced by ATRA in NB4-R1 cells infected with P30 expressing or control vector. Thus, we inferred that ATRA sensibility of NB4-R1 cells was enhanced by restoration of C/EBPα P42. In addition, we used histone deacetylase inhibitor trichostatin (TSA) to restore C/EBPα expression in NB4-R1 cells. Similar enhancement of myeloid differentiation and cell growth arrest were detected. Together, this study demonstrated that suppression of C/EBPα P42 induced by PI3K/Akt/mTOR inhibition impaired the differentiation and ATRA sensibility of APL cells. Restoring C/EBPα P42 is an attractive approach for differentiation therapy in ATRA resistant APL. Disclosures No relevant conflicts of interest to declare.

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

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.

Improvement of prognosis in refractory and relapsed acute promyelocytic leukemia over recent years: the role of all- trans retinoic acid therapy

1997 ◽  
Vol 75 (5-6) ◽  
pp. 195-200 ◽  
Author(s):  
X. Thomas ◽  
B. Anglaret ◽  
A. Thiebaut ◽  
A. Belhabri ◽  
D. Treille-Ritouet ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Acute Promyelocytic Leukemia ◽  
Promyelocytic Leukemia ◽  
Acid Therapy ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid

Hypercalcemia associated with all-trans-retinoic acid in the treatment of acute promyelocytic leukemia

1993 ◽  
Vol 17 (5) ◽  
pp. 441-443 ◽  
Author(s):  
Masae Sakakibara ◽  
Motoki Ichikawa ◽  
Yoshiro Amano ◽  
Shigeyuki Matsuzawa ◽  
Kazunaga Agematsu ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Acute Promyelocytic Leukemia ◽  
Promyelocytic Leukemia ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid

GENITAL ULCERS AFTER TREATMENT WITH ALL-trans-RETINOIC ACID IN A CHILD WITH ACUTE PROMYELOCYTIC LEUKEMIA

2005 ◽  
Vol 22 (5) ◽  
pp. 357-359 ◽  
Author(s):  
Selma Ünal ◽  
Fatma Gümrük ◽  
Mualla Çetin ◽  
Gönül Hiçsönmez
Keyword(s):  
Retinoic Acid ◽  
Acute Promyelocytic Leukemia ◽  
Promyelocytic Leukemia ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Genital Ulcers

All-trans retinoic acid and short-time, high-dose cytarabine in two children with acute promyelocytic leukemia

1996 ◽  
Vol 26 (4) ◽  
pp. 254-257 ◽  
Author(s):  
Klaus Schmitt ◽  
Andreas Zoubek ◽  
Rudolf Schwarz ◽  
Gerald Tulzer ◽  
Elisabeth Koller ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Acute Promyelocytic Leukemia ◽  
Promyelocytic Leukemia ◽  
High Dose ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
High Dose Cytarabine ◽  
Short Time
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