PMID- 7519122
OWN - NLM
STAT- MEDLINE
DCOM- 19940831
LR  - 20171116
IS  - 0008-5472 (Print)
IS  - 0008-5472 (Linking)
VI  - 54
IP  - 16
DP  - 1994 Aug 15
TI  - PML/RAR alpha+ U937 mutant and NB4 cell lines: retinoic acid restores the 
      monocytic differentiation response to vitamin D3.
PG  - 4508-15
AB  - We have analyzed the differentiation program of a U937 promonocytic leukemia 
      clone transduced with the acute promyelocytic leukemia specific PML/RAR alpha 
      fusion gene, the expression of which is under the control of the inducible 
      metallothionine (MT) I promoter (MTPR9 clone). MTPR9 cells treated with Zn2+ 
      hence exhibit levels of PML-RAR alpha protein as high as fresh acute 
      promyelocytic leukemia blasts. In the absence of Zn2+, i.e., upon low level 
      PML/RAR alpha expression, 1,25-dihydroxyvitamin D3 (D3) and particularly D3 plus 
      transforming growth factor beta 1 (TGF-beta 1) induced terminal differentiation 
      of MTPR9 cells (as observed in "wild-type" U937 cells), on the basis of 
      morphology, membrane antigen pattern, and functional criteria. Conversely, in the 
      presence of Zn2+, D3 and D3 plus TGF-beta 1 failed to induce terminal 
      differentiation, as evaluated by the above parameters. Interestingly, retinoic 
      acid (RA) treatment suppresses the differentiation blockade induced by high level 
      PML-RAR alpha protein; indeed, Zn(2+)-treated MTPR9 cells incubated with RA plus 
      D3 exhibited significant terminal monocytic maturation, comparable to that of 
      cells treated with D3 alone or combined with RA in absence of Zn2+. Similar 
      observations were made in NB4, a PML-RAR+ human acute leukemic line. As expected 
      RA treatment of NB4 cells causes granulocytic differentiation. Interestingly, the 
      cell line is only scarcely induced to mature monocytic cells by D3 or D3 plus 
      TGF-beta 1 treatment, whereas it is effectively induced to monocytic maturation 
      by combined treatment with D3 and RA. Accordingly, the rate of NB4 cell 
      proliferation is only slightly affected by D3 or D3 plus TGF-beta 1 treatment, 
      mildly inhibited by RA, and markedly decreased by D3 plus RA. These results 
      indicate that in both U937 and NB4 cells high level PML/RAR alpha expression 
      inhibits the monocytic terminal differentiation program triggered by D3 or D3 
      plus TGF-beta 1, whereas RA treatment effectively antagonizes this inhibitory 
      PML-RAR alpha action and restores the D3 differentiative effect.
FAU - Testa, U
AU  - Testa U
AD  - Department of Hematology and Oncology, Istituto Superiore di Sanita, Rome, Italy.
FAU - Grignani, F
AU  - Grignani F
FAU - Barberi, T
AU  - Barberi T
FAU - Fagioli, M
AU  - Fagioli M
FAU - Masciulli, R
AU  - Masciulli R
FAU - Ferrucci, P F
AU  - Ferrucci PF
FAU - Seripa, D
AU  - Seripa D
FAU - Camagna, A
AU  - Camagna A
FAU - Alcalay, M
AU  - Alcalay M
FAU - Pelicci, P G
AU  - Pelicci PG
AU  - et al.
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (Antigens, CD)
RN  - 0 (Antigens, Differentiation, Myelomonocytic)
RN  - 0 (Lipopolysaccharide Receptors)
RN  - 0 (Lipopolysaccharides)
RN  - 0 (Neoplasm Proteins)
RN  - 0 (Nuclear Proteins)
RN  - 0 (Promyelocytic Leukemia Protein)
RN  - 0 (Transcription Factors)
RN  - 0 (Transforming Growth Factor beta)
RN  - 0 (Tumor Suppressor Proteins)
RN  - 143220-95-5 (PML protein, human)
RN  - 1C6V77QF41 (Cholecalciferol)
RN  - 5688UTC01R (Tretinoin)
RN  - J41CSQ7QDS (Zinc)
SB  - IM
GS  - PML/RAR&agr;
MH  - Antigens, CD/analysis
MH  - Antigens, Differentiation, Myelomonocytic/analysis
MH  - Cell Differentiation/drug effects/genetics
MH  - Cell Division/drug effects/genetics
MH  - Cholecalciferol/*pharmacology
MH  - Gene Expression Regulation, Leukemic
MH  - Humans
MH  - Leukemia, Promyelocytic, Acute/*genetics/metabolism/pathology
MH  - Lipopolysaccharide Receptors
MH  - Lipopolysaccharides/metabolism
MH  - *Neoplasm Proteins
MH  - *Nuclear Proteins
MH  - Promyelocytic Leukemia Protein
MH  - Transcription Factors/*metabolism
MH  - Transfection
MH  - Transforming Growth Factor beta/pharmacology
MH  - Tretinoin/*pharmacology
MH  - Tumor Cells, Cultured
MH  - Tumor Suppressor Proteins
MH  - Zinc/pharmacology
EDAT- 1994/08/15 00:00
MHDA- 1994/08/15 00:01
CRDT- 1994/08/15 00:00
PHST- 1994/08/15 00:00 [pubmed]
PHST- 1994/08/15 00:01 [medline]
PHST- 1994/08/15 00:00 [entrez]
PST - ppublish
SO  - Cancer Res. 1994 Aug 15;54(16):4508-15.