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. 1985 Jul;76(1):365–369. doi: 10.1172/JCI111970

In vivo differentiation of blast-phase chronic granulocytic leukemia. Expression of c-myc and c-abl protooncogenes.

C A Koller, V W Campbell, D A Polansky, A Mulhern, D M Miller
PMCID: PMC423784  PMID: 3160729

Abstract

A patient with chronic granulocytic leukemia in acute blastic transformation was treated with mithramycin, an RNA synthesis inhibitor, after in vitro exposure of her leukemic cells to mithramycin showed differentiation to normal appearing granulocytes. Mithramycin therapy in vivo resulted in a prompt and dramatic hematologic response. Before therapy, the patient's leukemic cells had high levels of transcription of the cellular myc and abl protooncogenes. After initiation of therapy, protooncogene mRNA decreased rapidly. These observations indicate that mithramycin can induce differentiation both in vitro and in vivo and suggest that such changes may be associated with altered oncogene expression.

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Selected References

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  1. Alitalo K., Schwab M., Lin C. C., Varmus H. E., Bishop J. M. Homogeneously staining chromosomal regions contain amplified copies of an abundantly expressed cellular oncogene (c-myc) in malignant neuroendocrine cells from a human colon carcinoma. Proc Natl Acad Sci U S A. 1983 Mar;80(6):1707–1711. doi: 10.1073/pnas.80.6.1707. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Berger S. L., Birkenmeier C. S. Inhibition of intractable nucleases with ribonucleoside--vanadyl complexes: isolation of messenger ribonucleic acid from resting lymphocytes. Biochemistry. 1979 Nov 13;18(23):5143–5149. doi: 10.1021/bi00590a018. [DOI] [PubMed] [Google Scholar]
  3. Buell G. N., Wickens M. P., Carbon J., Schimke R. T. Isolation of recombinant plasmids bearing cDNA to hen ovomucoid and lysozyme mRNAs. J Biol Chem. 1979 Sep 25;254(18):9277–9283. [PubMed] [Google Scholar]
  4. Bunte T., Greiser-Wilke I., Moelling K. The transforming protein of the MC29-related virus CMII is a nuclear DNA-binding protein whereas MH2 codes for a cytoplasmic RNA-DNA binding polyprotein. EMBO J. 1983;2(7):1087–1092. doi: 10.1002/j.1460-2075.1983.tb01550.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Böyum A. Isolation of mononuclear cells and granulocytes from human blood. Isolation of monuclear cells by one centrifugation, and of granulocytes by combining centrifugation and sedimentation at 1 g. Scand J Clin Lab Invest Suppl. 1968;97:77–89. [PubMed] [Google Scholar]
  6. Canellos G. P., DeVita V. T., Whang-Peng J., Chabner B. A., Schein P. S., Young R. C. Chemotherapy of the blastic phase of chronic granulocytic leukemia: hypodiploidy and response to therapy. Blood. 1976 Jun;47(6):1003–1009. [PubMed] [Google Scholar]
  7. Collins S. J., Bodner A., Ting R., Gallo R. C. Induction of morphological and functional differentiation of human promyelocytic leukemia cells (HL-60) by componuds which induce differentiation of murine leukemia cells. Int J Cancer. 1980 Feb 15;25(2):213–218. doi: 10.1002/ijc.2910250208. [DOI] [PubMed] [Google Scholar]
  8. Collins S., Groudine M. Amplification of endogenous myc-related DNA sequences in a human myeloid leukaemia cell line. Nature. 1982 Aug 12;298(5875):679–681. doi: 10.1038/298679a0. [DOI] [PubMed] [Google Scholar]
  9. Cooper G. M. Cellular transforming genes. Science. 1982 Aug 27;217(4562):801–806. doi: 10.1126/science.6285471. [DOI] [PubMed] [Google Scholar]
  10. Dalla-Favera R., Bregni M., Erikson J., Patterson D., Gallo R. C., Croce C. M. Human c-myc onc gene is located on the region of chromosome 8 that is translocated in Burkitt lymphoma cells. Proc Natl Acad Sci U S A. 1982 Dec;79(24):7824–7827. doi: 10.1073/pnas.79.24.7824. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Dalla-Favera R., Gelmann E. P., Martinotti S., Franchini G., Papas T. S., Gallo R. C., Wong-Staal F. Cloning and characterization of different human sequences related to the onc gene (v-myc) of avian myelocytomatosis virus (MC29). Proc Natl Acad Sci U S A. 1982 Nov;79(21):6497–6501. doi: 10.1073/pnas.79.21.6497. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Goff S. P., Witte O. N., Gilboa E., Rosenberg N., Baltimore D. Genome structure of Abelson murine leukemia virus variants: proviruses in fibroblasts and lymphoid cells. J Virol. 1981 May;38(2):460–468. doi: 10.1128/jvi.38.2.460-468.1981. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Goldman J. M., Lu D. P. New approaches in chronic granulocytic leukemia--origin, prognosis, and treatment. Semin Hematol. 1982 Oct;19(4):241–256. [PubMed] [Google Scholar]
  14. Gonda T. J., Sheiness D. K., Bishop J. M. Transcripts from the cellular homologs of retroviral oncogenes: distribution among chicken tissues. Mol Cell Biol. 1982 Jun;2(6):617–624. doi: 10.1128/mcb.2.6.617. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Griffin J. D., Todd R. F., 3rd, Ritz J., Nadler L. M., Canellos G. P., Rosenthal D., Gallivan M., Beveridge R. P., Weinstein H., Karp D. Differentiation patterns in the blastic phase of chronic myeloid leukemia. Blood. 1983 Jan;61(1):85–91. [PubMed] [Google Scholar]
  16. Heisterkamp N., Groffen J., Stephenson J. R., Spurr N. K., Goodfellow P. N., Solomon E., Carritt B., Bodmer W. F. Chromosomal localization of human cellular homologues of two viral oncogenes. Nature. 1982 Oct 21;299(5885):747–749. doi: 10.1038/299747a0. [DOI] [PubMed] [Google Scholar]
  17. Honma Y., Kasukabe T., Okabe J., Hozumi M. Prolongation of survival time of mice inoculated with myeloid leukemia cells by inducers of normal differentiation. Cancer Res. 1979 Aug;39(8):3167–3171. [PubMed] [Google Scholar]
  18. Hozumi M. Fundamentals of chemotherapy of myeloid leukemia by induction of leukemia cell differentiation. Adv Cancer Res. 1983;38:121–169. doi: 10.1016/s0065-230x(08)60189-x. [DOI] [PubMed] [Google Scholar]
  19. Kelly K., Cochran B. H., Stiles C. D., Leder P. Cell-specific regulation of the c-myc gene by lymphocyte mitogens and platelet-derived growth factor. Cell. 1983 Dec;35(3 Pt 2):603–610. doi: 10.1016/0092-8674(83)90092-2. [DOI] [PubMed] [Google Scholar]
  20. Koeffler H. P. Induction of differentiation of human acute myelogenous leukemia cells: therapeutic implications. Blood. 1983 Oct;62(4):709–721. [PubMed] [Google Scholar]
  21. Land H., Parada L. F., Weinberg R. A. Tumorigenic conversion of primary embryo fibroblasts requires at least two cooperating oncogenes. Nature. 1983 Aug 18;304(5927):596–602. doi: 10.1038/304596a0. [DOI] [PubMed] [Google Scholar]
  22. Little C. D., Nau M. M., Carney D. N., Gazdar A. F., Minna J. D. Amplification and expression of the c-myc oncogene in human lung cancer cell lines. Nature. 1983 Nov 10;306(5939):194–196. doi: 10.1038/306194a0. [DOI] [PubMed] [Google Scholar]
  23. McCarthy D. M., Rassool F. V., Goldman J. M., Graham S. V., Birnie G. D. Genomic alterations involving the c-myc proto-oncogene locus during the evolution of a case of chronic granulocytic leukaemia. Lancet. 1984 Dec 15;2(8416):1362–1365. doi: 10.1016/s0140-6736(84)92058-0. [DOI] [PubMed] [Google Scholar]
  24. Persson H., Leder P. Nuclear localization and DNA binding properties of a protein expressed by human c-myc oncogene. Science. 1984 Aug 17;225(4663):718–721. doi: 10.1126/science.6463648. [DOI] [PubMed] [Google Scholar]
  25. Reitsma P. H., Rothberg P. G., Astrin S. M., Trial J., Bar-Shavit Z., Hall A., Teitelbaum S. L., Kahn A. J. Regulation of myc gene expression in HL-60 leukaemia cells by a vitamin D metabolite. Nature. 1983 Dec 1;306(5942):492–494. doi: 10.1038/306492a0. [DOI] [PubMed] [Google Scholar]
  26. Rowley J. D. Biological implications of consistent chromosome rearrangements in leukemia and lymphoma. Cancer Res. 1984 Aug;44(8):3159–3168. [PubMed] [Google Scholar]
  27. Rowley J. D. Letter: A new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining. Nature. 1973 Jun 1;243(5405):290–293. doi: 10.1038/243290a0. [DOI] [PubMed] [Google Scholar]
  28. Taub R., Kirsch I., Morton C., Lenoir G., Swan D., Tronick S., Aaronson S., Leder P. Translocation of the c-myc gene into the immunoglobulin heavy chain locus in human Burkitt lymphoma and murine plasmacytoma cells. Proc Natl Acad Sci U S A. 1982 Dec;79(24):7837–7841. doi: 10.1073/pnas.79.24.7837. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Thomas P. S. Hybridization of denatured RNA and small DNA fragments transferred to nitrocellulose. Proc Natl Acad Sci U S A. 1980 Sep;77(9):5201–5205. doi: 10.1073/pnas.77.9.5201. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Watson D. K., Psallidopoulos M. C., Samuel K. P., Dalla-Favera R., Papas T. S. Nucleotide sequence analysis of human c-myc locus, chicken homologue, and myelocytomatosis virus MC29 transforming gene reveals a highly conserved gene product. Proc Natl Acad Sci U S A. 1983 Jun;80(12):3642–3645. doi: 10.1073/pnas.80.12.3642. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Yang A., Miller D. M. Purification of functional RNA from human granulocytes. J Lab Clin Med. 1985 Jan;105(1):94–98. [PubMed] [Google Scholar]
  32. Yarbro J. W., Kennedy B. J., Barnum C. P. Mithramycin inhibition of ribonucleic acid synthesis. Cancer Res. 1966 Jan;26(1):36–39. [PubMed] [Google Scholar]
  33. Yunis J. J. The chromosomal basis of human neoplasia. Science. 1983 Jul 15;221(4607):227–236. doi: 10.1126/science.6336310. [DOI] [PubMed] [Google Scholar]
  34. de Klein A., van Kessel A. G., Grosveld G., Bartram C. R., Hagemeijer A., Bootsma D., Spurr N. K., Heisterkamp N., Groffen J., Stephenson J. R. A cellular oncogene is translocated to the Philadelphia chromosome in chronic myelocytic leukaemia. Nature. 1982 Dec 23;300(5894):765–767. doi: 10.1038/300765a0. [DOI] [PubMed] [Google Scholar]

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