Article

Combination of retinoic acid and tumor necrosis factor overcomes the maturation block in a variety of retinoic acid-resistant acute promyelocytic leukemia cells.

Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, McGill University, Montreal, Quebec, Canada.
Blood (impact factor: 9.9). 12/2004; 104(10):3335-42. DOI:10.1182/blood-2004-01-0023 pp.3335-42
Source: PubMed

ABSTRACT Retinoic acid (RA) overcomes the maturation block in t(15:17) acute promyelocytic leukemia (APL), leading to granulocytic differentiation. Patients receiving RA alone invariably develop RA resistance. RA-resistant cells can serve as useful models for the development of treatments for both APL and other leukemias. Previously, we showed that RA and tumor necrosis factor (TNF) promote monocytic differentiation of the APL cell line NB4 and U937 monoblastic cells. Here, we report that combining TNF with RA leads to maturation of several RA-resistant APL cells along a monocytic pathway, whereas UF-1, a patient-derived RA-resistant cell line, showed characteristics of granulocytic differentiation. We found distinct differences in gene regulation between UF-1 cells and cells showing monocytic differentiation. Although IRF-7 was up-regulated by TNF and RA in all cells tested, expression of c-jun and PU.1 correlated with monocytic differentiation. Furthermore, synergistic induction of PU.1 DNA binding and macrophage colony-stimulating factor receptor (m-CSF-1R) mRNA was observed only in cells differentiating into monocytes. Using neutralizing antibodies against m-CSF-1R or its ligand, we found that inhibiting this pathway strongly reduced CD14 expression in response to RA and TNF, suggesting that this pathway is essential for their synergy in RA-resistant leukemia cells.

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Keywords

APL cell line NB4
 
combining TNF
 
distinct differences
 
gene regulation
 
granulocytic differentiation
 
macrophage colony-stimulating factor receptor
 
maturation block
 
monocytic pathway
 
neutralizing antibodies
 
patient-derived RA-resistant cell line
 
PU.1 correlated
 
PU.1 DNA binding
 
RA resistance
 
RA-resistant APL cells
 
RA-resistant cells
 
RA-resistant leukemia cells
 
synergistic induction
 
tumor necrosis factor
 
U937 monoblastic cells
 
UF-1 cells
 

Michael Witcher