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. 1994 Aug;145(2):338–344.

p53 expression in myeloid cells of myelodysplastic syndromes. Association with evolution of overt leukemia.

M Kitagawa 1, S Yoshida 1, T Kuwata 1, T Tanizawa 1, R Kamiyama 1
PMCID: PMC1887403  PMID: 8053492

Abstract

To assess p53 expression in the hematopoietic cells of the bone marrow in premalignant as well as malignant conditions, we examined immunohistochemically bone marrow biopsies from patients with myelodysplastic syndromes (MDS, n = 51), acute myeloid leukemia (n = 42) and as a nonneoplastic condition, aplastic anemia (n = 20) and samples from individuals who had no hematological disorder (control, n = 12). Nuclear accumulation of p53 protein was found in seven of 51 patients with MDS (14%) and two of 42 acute myeloid leukemia patients (5%), whereas patients with aplastic anemia and control subjects were uniformly negative for p53 protein. In the bone marrow of patient with MDS, p53-positive cells constituted about 5 to 30% of the total bone marrow cells. Two-color immunohistochemical analysis revealed that the p53-positive cells were also positive for the myeloid cell marker. Half of the MDS cases that evolved to overt leukemia (seven of 14) exhibited positive p53 reaction in the bone marrow at the time of initial diagnosis. This frequency (50%) was significantly higher than that in de novo acute myeloid leukemia cases. All of the seven MDS cases that exhibited p53 expression at the time of initial diagnosis developed overt leukemia later, and p53 expression was maintained throughout the progression of MDS. The results suggest that p53 mutations that occur in the myeloid cells in MDS may confer a growth advantage to these cells resulting in the progression to overt leukemia. Thus, immunohistochemical examination for p53 is very useful for predicting the evolution to overt leukemia from MDS.

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Selected References

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  1. Baker S. J., Fearon E. R., Nigro J. M., Hamilton S. R., Preisinger A. C., Jessup J. M., vanTuinen P., Ledbetter D. H., Barker D. F., Nakamura Y. Chromosome 17 deletions and p53 gene mutations in colorectal carcinomas. Science. 1989 Apr 14;244(4901):217–221. doi: 10.1126/science.2649981. [DOI] [PubMed] [Google Scholar]
  2. Baker S. J., Markowitz S., Fearon E. R., Willson J. K., Vogelstein B. Suppression of human colorectal carcinoma cell growth by wild-type p53. Science. 1990 Aug 24;249(4971):912–915. doi: 10.1126/science.2144057. [DOI] [PubMed] [Google Scholar]
  3. Bennett J. M., Catovsky D., Daniel M. T., Flandrin G., Galton D. A., Gralnick H. R., Sultan C. Proposals for the classification of the myelodysplastic syndromes. Br J Haematol. 1982 Jun;51(2):189–199. [PubMed] [Google Scholar]
  4. Bennett J. M., Catovsky D., Daniel M. T., Flandrin G., Galton D. A., Gralnick H. R., Sultan C. Proposed revised criteria for the classification of acute myeloid leukemia. A report of the French-American-British Cooperative Group. Ann Intern Med. 1985 Oct;103(4):620–625. doi: 10.7326/0003-4819-103-4-620. [DOI] [PubMed] [Google Scholar]
  5. Cesarman E., Inghirami G., Chadburn A., Knowles D. M. High levels of p53 protein expression do not correlate with p53 gene mutations in anaplastic large cell lymphoma. Am J Pathol. 1993 Sep;143(3):845–856. [PMC free article] [PubMed] [Google Scholar]
  6. Clarke C. F., Cheng K., Frey A. B., Stein R., Hinds P. W., Levine A. J. Purification of complexes of nuclear oncogene p53 with rat and Escherichia coli heat shock proteins: in vitro dissociation of hsc70 and dnaK from murine p53 by ATP. Mol Cell Biol. 1988 Mar;8(3):1206–1215. doi: 10.1128/mcb.8.3.1206. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Eliyahu D., Goldfinger N., Pinhasi-Kimhi O., Shaulsky G., Skurnik Y., Arai N., Rotter V., Oren M. Meth A fibrosarcoma cells express two transforming mutant p53 species. Oncogene. 1988 Sep;3(3):313–321. [PubMed] [Google Scholar]
  8. Feinstein E., Cimino G., Gale R. P., Alimena G., Berthier R., Kishi K., Goldman J., Zaccaria A., Berrebi A., Canaani E. p53 in chronic myelogenous leukemia in acute phase. Proc Natl Acad Sci U S A. 1991 Jul 15;88(14):6293–6297. doi: 10.1073/pnas.88.14.6293. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Fenaux P., Jonveaux P., Quiquandon I., Laï J. L., Pignon J. M., Loucheux-Lefebvre M. H., Bauters F., Berger R., Kerckaert J. P. P53 gene mutations in acute myeloid leukemia with 17p monosomy. Blood. 1991 Oct 1;78(7):1652–1657. [PubMed] [Google Scholar]
  10. Finlay C. A., Hinds P. W., Levine A. J. The p53 proto-oncogene can act as a suppressor of transformation. Cell. 1989 Jun 30;57(7):1083–1093. doi: 10.1016/0092-8674(89)90045-7. [DOI] [PubMed] [Google Scholar]
  11. Finlay C. A., Hinds P. W., Tan T. H., Eliyahu D., Oren M., Levine A. J. Activating mutations for transformation by p53 produce a gene product that forms an hsc70-p53 complex with an altered half-life. Mol Cell Biol. 1988 Feb;8(2):531–539. doi: 10.1128/mcb.8.2.531. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Gaidano G., Guerrasio A., Serra A., Carozzi F., Cambrin G. R., Petroni D., Saglio G. Mutations in the P53 and RAS family genes are associated with tumor progression of BCR/ABL negative chronic myeloproliferative disorders. Leukemia. 1993 Jul;7(7):946–953. [PubMed] [Google Scholar]
  13. Hall P. A., McKee P. H., Menage H. D., Dover R., Lane D. P. High levels of p53 protein in UV-irradiated normal human skin. Oncogene. 1993 Jan;8(1):203–207. [PubMed] [Google Scholar]
  14. Hollstein M., Sidransky D., Vogelstein B., Harris C. C. p53 mutations in human cancers. Science. 1991 Jul 5;253(5015):49–53. doi: 10.1126/science.1905840. [DOI] [PubMed] [Google Scholar]
  15. Iggo R., Gatter K., Bartek J., Lane D., Harris A. L. Increased expression of mutant forms of p53 oncogene in primary lung cancer. Lancet. 1990 Mar 24;335(8691):675–679. doi: 10.1016/0140-6736(90)90801-b. [DOI] [PubMed] [Google Scholar]
  16. Jonveaux P., Fenaux P., Quiquandon I., Pignon J. M., Laï J. L., Loucheux-Lefebvre M. H., Goossens M., Bauters F., Berger R. Mutations in the p53 gene in myelodysplastic syndromes. Oncogene. 1991 Dec;6(12):2243–2247. [PubMed] [Google Scholar]
  17. Kitagawa M., Kamiyama R., Kasuga T. Expression of the proliferating cell nuclear antigen in bone marrow cells from patients with myelodysplastic syndromes and aplastic anemia. Hum Pathol. 1993 Apr;24(4):359–363. doi: 10.1016/0046-8177(93)90082-r. [DOI] [PubMed] [Google Scholar]
  18. Kitagawa M., Kamiyama R., Kasuga T. Increase in number of bone marrow macrophages in patients with myelodysplastic syndromes. Eur J Haematol. 1993 Jul;51(1):56–58. doi: 10.1111/j.1600-0609.1993.tb00608.x. [DOI] [PubMed] [Google Scholar]
  19. Kitagawa M., Kamiyama R., Takemura T., Kasuga T. Bone marrow analysis of the myelodysplastic syndromes: histological and immunohistochemical features related to the evolution of overt leukemia. Virchows Arch B Cell Pathol Incl Mol Pathol. 1989;57(1):47–53. doi: 10.1007/BF02899064. [DOI] [PubMed] [Google Scholar]
  20. Koizumi S., Fisher R. J., Fujiwara S., Jorcyk C., Bhat N. K., Seth A., Papas T. S. Isoforms of the human ets-1 protein: generation by alternative splicing and differential phosphorylation. Oncogene. 1990 May;5(5):675–681. [PubMed] [Google Scholar]
  21. Lane D. P. Cancer. p53, guardian of the genome. Nature. 1992 Jul 2;358(6381):15–16. doi: 10.1038/358015a0. [DOI] [PubMed] [Google Scholar]
  22. Levine A. J., Momand J., Finlay C. A. The p53 tumour suppressor gene. Nature. 1991 Jun 6;351(6326):453–456. doi: 10.1038/351453a0. [DOI] [PubMed] [Google Scholar]
  23. Ludwig L., Schulz A. S., Janssen J. W., Grünewald K., Bartram C. R. P53 mutations in myelodysplastic syndromes. Leukemia. 1992 Dec;6(12):1302–1304. [PubMed] [Google Scholar]
  24. Mercer W. E., Shields M. T., Amin M., Sauve G. J., Appella E., Romano J. W., Ullrich S. J. Negative growth regulation in a glioblastoma tumor cell line that conditionally expresses human wild-type p53. Proc Natl Acad Sci U S A. 1990 Aug;87(16):6166–6170. doi: 10.1073/pnas.87.16.6166. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Momand J., Zambetti G. P., Olson D. C., George D., Levine A. J. The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation. Cell. 1992 Jun 26;69(7):1237–1245. doi: 10.1016/0092-8674(92)90644-r. [DOI] [PubMed] [Google Scholar]
  26. Rivas C. I., Wisniewski D., Strife A., Perez A., Lambek C., Bruno S., Darzynkiewicz Z., Clarkson B. Constitutive expression of p53 protein in enriched normal human marrow blast cell populations. Blood. 1992 Apr 15;79(8):1982–1986. [PubMed] [Google Scholar]
  27. Slingerland J. M., Minden M. D., Benchimol S. Mutation of the p53 gene in human acute myelogenous leukemia. Blood. 1991 Apr 1;77(7):1500–1507. [PubMed] [Google Scholar]
  28. Stürzbecher H. W., Chumakov P., Welch W. J., Jenkins J. R. Mutant p53 proteins bind hsp 72/73 cellular heat shock-related proteins in SV40-transformed monkey cells. Oncogene. 1987 May;1(2):201–211. [PubMed] [Google Scholar]
  29. Sugimoto K., Hirano N., Toyoshima H., Chiba S., Mano H., Takaku F., Yazaki Y., Hirai H. Mutations of the p53 gene in myelodysplastic syndrome (MDS) and MDS-derived leukemia. Blood. 1993 Jun 1;81(11):3022–3026. [PubMed] [Google Scholar]
  30. Suzuki Y., Orita M., Shiraishi M., Hayashi K., Sekiya T. Detection of ras gene mutations in human lung cancers by single-strand conformation polymorphism analysis of polymerase chain reaction products. Oncogene. 1990 Jul;5(7):1037–1043. [PubMed] [Google Scholar]
  31. Vogelstein B. Cancer. A deadly inheritance. Nature. 1990 Dec 20;348(6303):681–682. doi: 10.1038/348681a0. [DOI] [PubMed] [Google Scholar]
  32. Vähäkangas K. H., Samet J. M., Metcalf R. A., Welsh J. A., Bennett W. P., Lane D. P., Harris C. C. Mutations of p53 and ras genes in radon-associated lung cancer from uranium miners. Lancet. 1992 Mar 7;339(8793):576–580. doi: 10.1016/0140-6736(92)90866-2. [DOI] [PubMed] [Google Scholar]
  33. Wynford-Thomas D. P53 in tumour pathology: can we trust immunocytochemistry? J Pathol. 1992 Apr;166(4):329–330. doi: 10.1002/path.1711660402. [DOI] [PubMed] [Google Scholar]
  34. Zambetti G. P., Levine A. J. A comparison of the biological activities of wild-type and mutant p53. FASEB J. 1993 Jul;7(10):855–865. doi: 10.1096/fasebj.7.10.8344485. [DOI] [PubMed] [Google Scholar]

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