Common defects of different retinoic acid resistant promyelocytic leukemia cells are persistent telomerase activity and nuclear body disorganization

Differentiation. 1997 Aug;61(5):321-31. doi: 10.1046/j.1432-0436.1997.6150321.x.


The acute promyelocytic leukemia (APL) t(15;17) rearrangement fuses the promyelocytic leukemia (PML) gene to the retinoic acid receptor-alpha (RAR alpha). There is expression of the chimeric transcript, PML/RAR alpha, in these APL cells. These clinical APL cases respond to the differentiation agent all-trans retinoic acid (ATRA) with complete but not durable remissions because ATRA resistance develops. The NB4 APL cell line expresses PML/RAR alpha and responds to the growth inhibitory and differentiation-inducing signals of ATRA. To identify mechanisms responsible for ATRA resistance in APL, ATRA-resistant NB4 cell lines were derived from parental NB4 cells using different strategies. These lines were resistant to the growth inhibition and differentiation effects of ATRA. ATRA-resistant cells were isolated as a de novo resistant line from parental NB4 cells (NB4-R1), following chemical mutagenization and selection in ATRA (NB4-R2), or after chronic selection in ATRA (NB4-R3). Common defects linked to this ATRA resistance were found. When cultured in ATRA, these resistant cells still express PML, RAR alpha, and PML/RAR alpha proteins. Sequence abnormalities were not detected in the RAR alpha DNA binding domains cloned from a representative RA-resistant NB4 line. In ATRA-sensitive but not ATRA-resistant NB4 cells, ATRA down-regulated retinoid X receptor-alpha (RXR alpha) expression, a known marker of ATRA response in parental NB4 cells. Notably, engineered overexpression of RXR alpha in ATRA-sensitive NB4 cells did not block ATRA-mediated growth suppression. ATRA treatment of these resistant NB4 lines did not signal a decline in telomerase activity or reorganization of PML-associated nuclear bodies, but both events occurred in ATRA-sensitive NB4 cells. These ATRA-resistant NB4 lines are not fully differentiation-defective, since monocytic maturation was induced following treatment with phorbol 12-myristate 13-acetate (PMA) and 1,25 dihydroxy vitamin D3 (vitamin D3). Notably, induced monocytic differentiation of these distinct ATRA-resistant APL lines markedly repressed telomerase activity. Thus, this study suggests that persistent telomerase activity and nuclear body disorganization are linked to ATRA resistance in APL.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Binding Sites
  • Blotting, Western
  • Carcinogens
  • Cell Differentiation / physiology
  • Cell Division / drug effects
  • Cell Nucleus / ultrastructure
  • Cholecalciferol / pharmacology
  • Clone Cells
  • DNA, Neoplasm / metabolism
  • Drug Resistance, Neoplasm
  • Humans
  • Leukemia, Promyelocytic, Acute / drug therapy
  • Leukemia, Promyelocytic, Acute / enzymology*
  • Leukemia, Promyelocytic, Acute / pathology*
  • Methylnitronitrosoguanidine
  • Polymerase Chain Reaction
  • Receptors, Retinoic Acid / biosynthesis
  • Retinoic Acid Receptor alpha
  • Telomerase / metabolism*
  • Tetradecanoylphorbol Acetate / pharmacology
  • Transcription, Genetic
  • Tretinoin / pharmacology*
  • Tumor Cells, Cultured


  • Antineoplastic Agents
  • Carcinogens
  • DNA, Neoplasm
  • RARA protein, human
  • Receptors, Retinoic Acid
  • Retinoic Acid Receptor alpha
  • Methylnitronitrosoguanidine
  • Cholecalciferol
  • Tretinoin
  • Telomerase
  • Tetradecanoylphorbol Acetate