Skip to main content
NCBI home page
The American Journal of Pathology logoLink to The American Journal of Pathology
. 1996 Dec;149(6):2023–2035.

Heterogeneous nuclear expression of the promyelocytic leukemia (PML) protein in normal and neoplastic human tissues.

M Gambacorta 1, L Flenghi 1, M Fagioli 1, S Pileri 1, L Leoncini 1, B Bigerna 1, R Pacini 1, L N Tanci 1, L Pasqualucci 1, S Ascani 1, A Mencarelli 1, A Liso 1, P G Pelicci 1, B Falini 1
PMCID: PMC1865355  PMID: 8952536

Abstract

The RING-finger promyelocytic leukemia (PML) protein is the product of the PML gene that fuses with the retinoic acid receptor-alpha gene in the t(15; 17) translocation of acute promyelocytic leukemia. Wild-type PML localizes in the nucleus with a typical speckled pattern that is a consequence of the concentration of the protein within discrete subnuclear domains known as nuclear bodies. Delocalization of PML from nuclear bodies has been documented in acute promyelocytic leukemia cells and suggested to contribute to leukemogenesis. In an attempt to get new insights into the function of the wild-type PML protein and to investigate whether it displays an altered expression pattern in neoplasms other than acute promyelocytic leukemia, we stained a large number of normal and neoplastic human tissues with a new murine monoclonal antibody (PG-M3) directed against the amino-terminal region of PML. As the PG-M3 epitope is partially resistant to fixatives, only cells that overexpress PML are detected by the antibody in microwave-heated paraffin sections. Among normal tissues, PML was characteristically up-regulated in activated epithelioid histiocytes and fibroblasts in a variety of pathological conditions, columnar epithelium in small active thyroid follicles, well differentiated foamy cells in the center of sebaceous glands, and hypersecretory endometria (Arias-Stella). Interferons, the PML of which is a primary target gene, and estrogens are likely to represent some of the cytokines and/or hormones that may be involved in the up-regulation of PML under these circumstances. In keeping with this concept, we found that PML is frequently overexpressed in Hodgkin and Reed-Sternberg cells of Hodgkin's disease, a tumor of cytokine-producing cells. Among solid tumors, overexpression of PML was frequently found in carcinomas of larynx and thyroid (papillary), epithelial thymomas, and Kaposi's sarcoma, whereas carcinomas of the lung, thyroid (follicular), breast, and colon were frequently negative or weakly PML+. We did not observe any changes in the levels of PML expression as the lesion progressed from benign dysplasia to carcinoma. Our immunohistological data are consistent with the hypothesized growth suppressor function of PML and strongly suggest that PML expression levels are likely to be modulated by a variety of stimuli, including cytokines and hormones.

Full text

PDF
2023

Images in this article

2027Figure 1
on p.2027
2029Figure 2
on p.2029
2030Figure 3
on p.2030
2031Figure 4
on p.2031
2032Figure 5
on p.2032

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Alcalay M., Zangrilli D., Fagioli M., Pandolfi P. P., Mencarelli A., Lo Coco F., Biondi A., Grignani F., Pelicci P. G. Expression pattern of the RAR alpha-PML fusion gene in acute promyelocytic leukemia. Proc Natl Acad Sci U S A. 1992 Jun 1;89(11):4840–4844. doi: 10.1073/pnas.89.11.4840. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Alcalay M., Zangrilli D., Pandolfi P. P., Longo L., Mencarelli A., Giacomucci A., Rocchi M., Biondi A., Rambaldi A., Lo Coco F. Translocation breakpoint of acute promyelocytic leukemia lies within the retinoic acid receptor alpha locus. Proc Natl Acad Sci U S A. 1991 Mar 1;88(5):1977–1981. doi: 10.1073/pnas.88.5.1977. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Ascoli C. A., Maul G. G. Identification of a novel nuclear domain. J Cell Biol. 1991 Mar;112(5):785–795. doi: 10.1083/jcb.112.5.785. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Borden K. L., Boddy M. N., Lally J., O'Reilly N. J., Martin S., Howe K., Solomon E., Freemont P. S. The solution structure of the RING finger domain from the acute promyelocytic leukaemia proto-oncoprotein PML. EMBO J. 1995 Apr 3;14(7):1532–1541. doi: 10.1002/j.1460-2075.1995.tb07139.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Borrow J., Goddard A. D., Sheer D., Solomon E. Molecular analysis of acute promyelocytic leukemia breakpoint cluster region on chromosome 17. Science. 1990 Sep 28;249(4976):1577–1580. doi: 10.1126/science.2218500. [DOI] [PubMed] [Google Scholar]
  6. Brasch K., Ochs R. L. Nuclear bodies (NBs): a newly "rediscovered" organelle. Exp Cell Res. 1992 Oct;202(2):211–223. doi: 10.1016/0014-4827(92)90068-j. [DOI] [PubMed] [Google Scholar]
  7. Cattoretti G., Pileri S., Parravicini C., Becker M. H., Poggi S., Bifulco C., Key G., D'Amato L., Sabattini E., Feudale E. Antigen unmasking on formalin-fixed, paraffin-embedded tissue sections. J Pathol. 1993 Oct;171(2):83–98. doi: 10.1002/path.1711710205. [DOI] [PubMed] [Google Scholar]
  8. Cordell J. L., Falini B., Erber W. N., Ghosh A. K., Abdulaziz Z., MacDonald S., Pulford K. A., Stein H., Mason D. Y. Immunoenzymatic labeling of monoclonal antibodies using immune complexes of alkaline phosphatase and monoclonal anti-alkaline phosphatase (APAAP complexes). J Histochem Cytochem. 1984 Feb;32(2):219–229. doi: 10.1177/32.2.6198355. [DOI] [PubMed] [Google Scholar]
  9. Daniel M. T., Koken M., Romagné O., Barbey S., Bazarbachi A., Stadler M., Guillemin M. C., Degos L., Chomienne C., de Thé H. PML protein expression in hematopoietic and acute promyelocytic leukemia cells. Blood. 1993 Sep 15;82(6):1858–1867. [PubMed] [Google Scholar]
  10. Dyck J. A., Maul G. G., Miller W. H., Jr, Chen J. D., Kakizuka A., Evans R. M. A novel macromolecular structure is a target of the promyelocyte-retinoic acid receptor oncoprotein. Cell. 1994 Jan 28;76(2):333–343. doi: 10.1016/0092-8674(94)90340-9. [DOI] [PubMed] [Google Scholar]
  11. Fagioli M., Alcalay M., Pandolfi P. P., Venturini L., Mencarelli A., Simeone A., Acampora D., Grignani F., Pelicci P. G. Alternative splicing of PML transcripts predicts coexpression of several carboxy-terminally different protein isoforms. Oncogene. 1992 Jun;7(6):1083–1091. [PubMed] [Google Scholar]
  12. Falini B., Pileri S., Martelli M. F. Histological and immunohistological analysis of human lymphomas. Crit Rev Oncol Hematol. 1989;9(4):351–419. doi: 10.1016/s1040-8428(89)80018-6. [DOI] [PubMed] [Google Scholar]
  13. Falini B., Pileri S., Pizzolo G., Dürkop H., Flenghi L., Stirpe F., Martelli M. F., Stein H. CD30 (Ki-1) molecule: a new cytokine receptor of the tumor necrosis factor receptor superfamily as a tool for diagnosis and immunotherapy. Blood. 1995 Jan 1;85(1):1–14. [PubMed] [Google Scholar]
  14. Flenghi L., Fagioli M., Tomassoni L., Pileri S., Gambacorta M., Pacini R., Grignani F., Casini T., Ferrucci P. F., Martelli M. F. Characterization of a new monoclonal antibody (PG-M3) directed against the aminoterminal portion of the PML gene product: immunocytochemical evidence for high expression of PML proteins on activated macrophages, endothelial cells, and epithelia. Blood. 1995 Apr 1;85(7):1871–1880. [PubMed] [Google Scholar]
  15. Grignani F., Fagioli M., Alcalay M., Longo L., Pandolfi P. P., Donti E., Biondi A., Lo Coco F., Grignani F., Pelicci P. G. Acute promyelocytic leukemia: from genetics to treatment. Blood. 1994 Jan 1;83(1):10–25. [PubMed] [Google Scholar]
  16. Grignani F., Ferrucci P. F., Testa U., Talamo G., Fagioli M., Alcalay M., Mencarelli A., Grignani F., Peschle C., Nicoletti I. The acute promyelocytic leukemia-specific PML-RAR alpha fusion protein inhibits differentiation and promotes survival of myeloid precursor cells. Cell. 1993 Aug 13;74(3):423–431. doi: 10.1016/0092-8674(93)80044-f. [DOI] [PubMed] [Google Scholar]
  17. Gruss H. J., Brach M. A., Drexler H. G., Bonifer R., Mertelsmann R. H., Herrmann F. Expression of cytokine genes, cytokine receptor genes, and transcription factors in cultured Hodgkin and Reed-Sternberg cells. Cancer Res. 1992 Jun 15;52(12):3353–3360. [PubMed] [Google Scholar]
  18. Kakizuka A., Miller W. H., Jr, Umesono K., Warrell R. P., Jr, Frankel S. R., Murty V. V., Dmitrovsky E., Evans R. M. Chromosomal translocation t(15;17) in human acute promyelocytic leukemia fuses RAR alpha with a novel putative transcription factor, PML. Cell. 1991 Aug 23;66(4):663–674. doi: 10.1016/0092-8674(91)90112-c. [DOI] [PubMed] [Google Scholar]
  19. Koken M. H., Linares-Cruz G., Quignon F., Viron A., Chelbi-Alix M. K., Sobczak-Thépot J., Juhlin L., Degos L., Calvo F., de Thé H. The PML growth-suppressor has an altered expression in human oncogenesis. Oncogene. 1995 Apr 6;10(7):1315–1324. [PubMed] [Google Scholar]
  20. Koken M. H., Puvion-Dutilleul F., Guillemin M. C., Viron A., Linares-Cruz G., Stuurman N., de Jong L., Szostecki C., Calvo F., Chomienne C. The t(15;17) translocation alters a nuclear body in a retinoic acid-reversible fashion. EMBO J. 1994 Mar 1;13(5):1073–1083. doi: 10.1002/j.1460-2075.1994.tb06356.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Korioth F., Gieffers C., Maul G. G., Frey J. Molecular characterization of NDP52, a novel protein of the nuclear domain 10, which is redistributed upon virus infection and interferon treatment. J Cell Biol. 1995 Jul;130(1):1–13. doi: 10.1083/jcb.130.1.1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Lam Y. W., Ammerlaan W., O W. S., Kroese F., Opstelten D. Cell type- and differentiation stage-dependent expression of PML domains in rat, detected by monoclonal antibody HIS55. Exp Cell Res. 1995 Dec;221(2):344–356. doi: 10.1006/excr.1995.1384. [DOI] [PubMed] [Google Scholar]
  23. Lavau C., Marchio A., Fagioli M., Jansen J., Falini B., Lebon P., Grosveld F., Pandolfi P. P., Pelicci P. G., Dejean A. The acute promyelocytic leukaemia-associated PML gene is induced by interferon. Oncogene. 1995 Sep 7;11(5):871–876. [PubMed] [Google Scholar]
  24. Maul G. G., Guldner H. H., Spivack J. G. Modification of discrete nuclear domains induced by herpes simplex virus type 1 immediate early gene 1 product (ICP0). J Gen Virol. 1993 Dec;74(Pt 12):2679–2690. doi: 10.1099/0022-1317-74-12-2679. [DOI] [PubMed] [Google Scholar]
  25. Moore P. S., Chang Y. Detection of herpesvirus-like DNA sequences in Kaposi's sarcoma in patients with and without HIV infection. N Engl J Med. 1995 May 4;332(18):1181–1185. doi: 10.1056/NEJM199505043321801. [DOI] [PubMed] [Google Scholar]
  26. Mu Z. M., Chin K. V., Liu J. H., Lozano G., Chang K. S. PML, a growth suppressor disrupted in acute promyelocytic leukemia. Mol Cell Biol. 1994 Oct;14(10):6858–6867. doi: 10.1128/mcb.14.10.6858. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Pandolfi P. P., Alcalay M., Fagioli M., Zangrilli D., Mencarelli A., Diverio D., Biondi A., Lo Coco F., Rambaldi A., Grignani F. Genomic variability and alternative splicing generate multiple PML/RAR alpha transcripts that encode aberrant PML proteins and PML/RAR alpha isoforms in acute promyelocytic leukaemia. EMBO J. 1992 Apr;11(4):1397–1407. doi: 10.1002/j.1460-2075.1992.tb05185.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Ponder B. A., Wilkinson M. M. Inhibition of endogenous tissue alkaline phosphatase with the use of alkaline phosphatase conjugates in immunohistochemistry. J Histochem Cytochem. 1981 Aug;29(8):981–984. doi: 10.1177/29.8.7024402. [DOI] [PubMed] [Google Scholar]
  29. Shi S. R., Key M. E., Kalra K. L. Antigen retrieval in formalin-fixed, paraffin-embedded tissues: an enhancement method for immunohistochemical staining based on microwave oven heating of tissue sections. J Histochem Cytochem. 1991 Jun;39(6):741–748. doi: 10.1177/39.6.1709656. [DOI] [PubMed] [Google Scholar]
  30. Stansfeld A. G., Diebold J., Noel H., Kapanci Y., Rilke F., Kelényi G., Sundstrom C., Lennert K., van Unnik J. A., Mioduszewska O. Updated Kiel classification for lymphomas. Lancet. 1988 Feb 6;1(8580):292–293. doi: 10.1016/s0140-6736(88)90367-4. [DOI] [PubMed] [Google Scholar]
  31. Stuurman N., de Graaf A., Floore A., Josso A., Humbel B., de Jong L., van Driel R. A monoclonal antibody recognizing nuclear matrix-associated nuclear bodies. J Cell Sci. 1992 Apr;101(Pt 4):773–784. doi: 10.1242/jcs.101.4.773. [DOI] [PubMed] [Google Scholar]
  32. Szostecki C., Guldner H. H., Netter H. J., Will H. Isolation and characterization of cDNA encoding a human nuclear antigen predominantly recognized by autoantibodies from patients with primary biliary cirrhosis. J Immunol. 1990 Dec 15;145(12):4338–4347. [PubMed] [Google Scholar]
  33. Terris B., Baldin V., Dubois S., Degott C., Flejou J. F., Hénin D., Dejean A. PML nuclear bodies are general targets for inflammation and cell proliferation. Cancer Res. 1995 Apr 1;55(7):1590–1597. [PubMed] [Google Scholar]
  34. Vagner-Capodano A. M., Mauchamp J., Stahl A., Lissitzky S. Nucleolar budding and formation of nuclear bodies in cultured thyroid cells stimulated by thyrotropin, dibutyryl cyclic AMP, and prostaglandin E2. J Ultrastruct Res. 1980 Jan;70(1):37–51. doi: 10.1016/s0022-5320(80)90020-9. [DOI] [PubMed] [Google Scholar]
  35. Warrell R. P., Jr, de Thé H., Wang Z. Y., Degos L. Acute promyelocytic leukemia. N Engl J Med. 1993 Jul 15;329(3):177–189. doi: 10.1056/NEJM199307153290307. [DOI] [PubMed] [Google Scholar]
  36. Weis K., Rambaud S., Lavau C., Jansen J., Carvalho T., Carmo-Fonseca M., Lamond A., Dejean A. Retinoic acid regulates aberrant nuclear localization of PML-RAR alpha in acute promyelocytic leukemia cells. Cell. 1994 Jan 28;76(2):345–356. doi: 10.1016/0092-8674(94)90341-7. [DOI] [PubMed] [Google Scholar]
  37. Xie K., Lambie E. J., Snyder M. Nuclear dot antigens may specify transcriptional domains in the nucleus. Mol Cell Biol. 1993 Oct;13(10):6170–6179. doi: 10.1128/mcb.13.10.6170. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. de Thé H., Chomienne C., Lanotte M., Degos L., Dejean A. The t(15;17) translocation of acute promyelocytic leukaemia fuses the retinoic acid receptor alpha gene to a novel transcribed locus. Nature. 1990 Oct 11;347(6293):558–561. doi: 10.1038/347558a0. [DOI] [PubMed] [Google Scholar]
  39. de Thé H., Lavau C., Marchio A., Chomienne C., Degos L., Dejean A. The PML-RAR alpha fusion mRNA generated by the t(15;17) translocation in acute promyelocytic leukemia encodes a functionally altered RAR. Cell. 1991 Aug 23;66(4):675–684. doi: 10.1016/0092-8674(91)90113-d. [DOI] [PubMed] [Google Scholar]

Articles from The American Journal of Pathology are provided here courtesy of American Society for Investigative Pathology

RESOURCES