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Mechanisms ofall-trans retinoic acid-induced differentiation of acute promyelocytic leukemia cells

Journal of Biosciences volume 25, pages 275–284 (2000)Cite this article

Abstract

Retinoic acids (RA) play a key role in myeloid differentiation through their agonistic nuclear receptors (RARα/RXR) to modulate the expression of target genes. In acute promyelocytic leukemia (APL) cells with rearrangement of retinoic acid receptor α (RARα) (including: PML-RARα, PLZF-RARα, NPM-RARα, NuMA-RARα or STAT5b-RARα) as a result of chromosomal translocations, the RA signal pathway is disrupted and myeloid differentiation is arrested at the promyelocytic stage. Pharmacologic dosage ofall-trans retinoic acid (ATRA) directly modulates PML-RARα and its interaction with the nuclear receptor co-repressor complex, which restores the wild-type RARα/RXR regulatory pathway and induces the transcriptional expression of downstream genes. Analysing gene expression profiles in APL cells before and after ATRA treatment represents a useful approach to identify genes whose functions are involved in this new cancer treatment. A chronologically well coordinated modulation of ATRA-regulated genes has thus been revealed which seems to constitute a balanced functional network underlying decreased cellular proliferation, initiation and progression of maturation, and maintenance of cell survival before terminal differentiation.

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Abbreviations

Mel:

Murine erythroid leukemia

DMSO:

dimethylsulfoxide

HMBA:

hexamethylenebiacetamide

TPA:

phorbol ester 12-O-tetradecanoylphorbol-13-acetate

RA:

retinoic acid

ATRA:

all-trans RA

APL:

acute promyelocytic leukemia

CR:

complete remission

RARα:

RA receptor α

RXRs:

retinoid X receptors

VDRs:

vitamin D receptors

THRs:

thyroid hormone receptors

CoR:

co-repressor

CoA:

co-activator

RARE:

RA response element

N-CoR:

nuclear receptor CoR

SMRT:

silencing mediator of retinoid and thyroid receptor

HDAC:

histone deacetylase

CBP:

CREB binding protein

P300:

protein p300

P/CAF:

P300/CBP associated factor

P/CIP:

P300/CBP interaction protein

ACTR:

activator of thyroid hormone and retinoid

NcoA-1:

nuclear receptors coactivator-1

SRC-1:

steroid hormone receptor coactivator-1

HAT:

histone acetylase

NLS:

nuclear localization signal

PODs:

PML oncogenic domains

PLZF:

promyelocytic leukemia zinc finger

ZID:

zinc finger protein with interaction domain

POZ:

pox-virus and zinc finger

BTB:

broad complex, tramtrack, bric a brac

NPM:

nucleophosmin

NuMA:

nuclear mitotic apparatus

TSA:

tricostratin A

DD-PCR:

differential display-PCR

SSH:

suppression subtractive hybridization

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  1. Shanghai Institute of Hematology, Ruijin Hospital Affiliated to Shanghai Second Medical University, 197 Ruijin Road II, 200025, Shanghai, People's Republic of China

    Ji-Wang Zhang, Jian Gu, Zhen-Yi Wang, Sai-Juan Chen & Zhu Chen

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  4. Sai-Juan Chen
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Correspondence to Zhu Chen.

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Zhang, JW., Gu, J., Wang, ZY. et al. Mechanisms ofall-trans retinoic acid-induced differentiation of acute promyelocytic leukemia cells. J Biosci 25, 275–284 (2000). https://doi.org/10.1007/BF02703936

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  • DOI: https://doi.org/10.1007/BF02703936

Keywords

  • Acute promyelocytic leukemia
  • differentiation
  • retinoic acid