Abstract
Loss of the p53 gene alleles was investigated in 26 patients with Ph+BCR/ABL+ chronic myeloid leukemia (CML) by means of the polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) analysis using the restriction enzymeAccII. In all cases, peripheral blood and/or bone marrow samples were obtained at different times during the chronic phase of the disease and at blast crisis, and in some of them also at the accelerated phase. Of the 12 cases considered informative, 11 evolved into myeloid type blast crisis and one into a lymphoid blast crisis, whereas only two showed an i(17q) chromosome at cytogenetic study. In four of the 12 informative cases, a loss of one p53 gene allele was observed, in all cases coincident with the development of the accelerated phase or blast crisis. One patient with a deleted p53 gene allele, in whom it was possible to analyze the gene structure in the three CML evolutive phases (chronic and accelerated phases and blast crisis), showed loss of the p53 gene allele in both the accelerated and the biastic phase, but not during the chronic phase. On the other hand, one of the two cases with an i(17q) chromosome exhibited one allelic deletion of the p53 gene. Thus, the relatively frequent monoallelic deletion of the p53 gene coincident with the appearance of the blast crisis registered in the present study would support a possible role of the p53 gene alterations in the evolution of CML to its final stages.
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Ahuja HG, Bar-Eli M, Arlin Z, Advani S, Allen SL, Goldman J, Snyder D, Foti A, Cline M (1991) The spectrum of molecular alterations in the evolution of chronic myelocytic leukemia. J Clin Invest 87:2042–2047
Andrews DF, Collins SJ (1987) Heterogeneity in expression of the bcr-abl fusion transcript in CML blast crisis. Leukemia 1:718–724
Baker SJ, Preisinger AC, Jessup JM, Paraskeva C, Markowith S, Willson JKV, Hamilton S, Vogelstein B (1990) p53 Mutations occur in combination with 17p allelic deletions as late events in colorectal tumorogenesis. Cancer Res 50:7717–7722
Bi S, Lanza F, Goldman JM (1993) The abnormal p53 proteins expressed in CML cell lines are non-functional. Leukemia 7:1840–1845
Bi S, Lanza F, Goldman JM (1994) The involvement of “tumor suppressor” p53 in normal and chronic myelogenous leukemia hemopoiesis. Cancer Res 54:582–586
Chen SJ, Wang Q, Tong JH, Xie WJ, Cao Q, Cai JR, Li XS, Wang ZY, Chen Z, Larsen CJ, Berger R (1991) Monoallelic deletions of the p53 gene in Chinese patients with chronic myelogenous leukemia in blast crisis. Nouv Rev Fr Hematol 33:481–484
Cervantes F, Ballesta F, Milá M, Rozman C (1986) Cytogenetic studies in blast crisis of Ph-positive chronic granulocytic leukemia: results and prognostic evaluation in 52 patients. Cancer Genet Cytogenet 21:239–246
Cervantes F, Rozman M, Rosell J, Urbano-Ispizua A, Montserrat E, Rozman C (1990) A study of prognostic factors in blast crisis of Philadelphia chromosome-positive chronic myelogenous leukemia. Br J Haematol 76:27–32
Cline MJ, Jat PS, Foti A (1992) Molecular mechanisms in the evolution of chronic myelocytic leukemia. Leuk Lymphoma 7:283–287
Daley GQ, Van Etten RA, Baltimore D (1990) Induction of chronic myelogenous leukemia in mice by the p210bcr-abl gene of the Philadelphia chromosome. Science 247:824–830
De la Calle-Martín O, Fabregat V, Romero M, Soler J, Vives J, Yagüe J (1990) Acc II polymorphism of the p53 gene. Nucleic Acids Res 18:4963
Feinstein E, Cimino G, Gale RP, Alimena G, Berthier R, Kishi K, Goldman J, Zaccaria A, Berrebi A, Canaani EC (1991) p53 in chronic myelogenous leukemia in acute phase. Proc Natl Acad Sci USA 88:6293–6297
Fey MF, Pilkington SP, Summers C, Wainscoat JS (1987) Molecular diagnosis of haematological disorders using DNA from stored bone marrow slides. Br J Haematol 67:489–492
Foti A, Ahuja HG, Allen SL, Koduru P, Schuster MW, Schulman P, Bar-Eli M, Cline MJ (1991) Correlation between molecular and clinical events in the evolution of chronic myelocytic leukemia to blast crisis. Blood 77:2441–2444
Gaidano G, Ballerini P, Gong JZ, Inghirami G, Neri A, Newcomb EW, Magrath IT, Knowles DM, Dalla-Favera R (1991) p53 Mutations in human lymphoid malignancies: association with Burkitt lymphoma and chronic lymphocytic leukemia. Proc Natl Acad Sci USA 88:5413–5417
Gaidano G, Serra A, Guerrasio A, Rege-Cambrin G, Mazza U, Saglio G (1994) Genetic analysis of p53 and RB1 tumor-suppressor genes in blast crisis of chronic myeloid leukemia. Ann Hematol 68:3–7
Gale RP, Goldman JM (1988) Rapid progress in chronic myelogenous leukemia. Leukemia 2:321–324
Groffen J, Stephenson JR, Heisterkamp N, de Klein A, Bartram CR, Grosveld G (1984) Philadelphia chromosome breakpoints are clustered within a limited region, bcr, on chromosome 22. Cell 36:93–99
Hernández A, Hernández P, Corral L, Muñiz A, Alaez C, Espinosa E, Fernández O, Martinez G (1993) p53 Gene rearrangements in chronic myelocytic leukemia. Ann Hematol 66:81–83
ISCN (1985) An international system for human cytogenetic nomenclature. Cytogenet Cell Genet 21:309–404
Isobe M, Emanuel BS, Givol D, Oren M, Croce CM (1986) Localization of gene for human p53 tumor antigen to band 17pl3. Nature 320:84–86
Kantarjian HM, Dixon D, Keating MJ, Talpaz M, Walters RS, Mc Credie KB, Freireich EJ (1988) Characteristics of accelerated disease in chronic myelogenous leukemia. Cancer 61:1441–1446
Kelman Z, Prokocimer M, Peller S, Kahn Y, Rechavi G, Manor Y, Cohen A, Rotter V (1989) Rearrangements in the p53 gene in Philadelphia chromosome-positive chronic myelogenous leukemia. Blood 74:2318–2324
Koeffler HP, Golde DW (1981) Chronic myelogenous leukemia-new concepts. N Engl J Med 304:1201–1209
LeMaistre A, Lee MS, Talpaz M, Kantarjian HM, Freireich EJ, Deisseroth AB, Trujillo JM, Stass SA (1989) ras Oncogene mutations are rare late-stage events in chronic myelogenous leukemia. Blood 73:889–891
McCarthy DM, Goldman JM, Rasool FV, Graham SV, Birnie GD (1984) Genomic alterations involving the c-myc protooncogene during the evolution of a case of chronic granulocytic leukemia. Lancet 2:1362–1365
McLaughlin J, Chianese E, Witte ON (1987) In vitro transformation of immature hematopoietic cells by the p210 BCR/ ABL oncogene products of the Philadelphia chromosome. Proc Natl Acad Sci USA 84:6558–6562
Mashal R, Shtalrid M, Talpaz M, Kantarjian H, Smith L, Beran M, Cork A, Trujillo J, Gutterman J, Deisseroth A (1990) Rearrangements and expression of p53 in the chronic phase and blast crisis of chronic myelogenous leukemia. Blood 75:180–189
Mercer WE, Arignolo C, Baserga R (1984) Role of the p53 protein in cell proliferation as studied by microinjection of monoclonal antibodies. Moll Cell Biol 4:276–281
Mori N, Wada M, Yokota J, Terada M, Okada M, Tesamura M, Masuda M, Hoshino S, Motoji T, Oshimi K, Mizoguchi M (1992) Mutations of the p53 suppressor gene in haematologic neoplasms. Br J Haematol 81:235–240
Nakai H, Misawa S, Toguchida J, Yandell DW, Ishizaki K (1992) Frequent p53 gene mutations in blast crisis of chronic myelogenous leukemia, especially in myeloid crisis harboring loss of a chromosome 17p. Cancer Res 52:6588–6593
Neubauer A, He M, Schmidt CA, Huhn D, Liu ET (1993) Genetic alterations in the p53 gene in the blast crisis of chronic myelogenous leukemia: analysis by polymerase chain reaction-based techniques. Leukemia 7:593–600
Nigro JM, Baker SJ, Preisinger AC, Jessup JM, Hostetter R, Cleary K, Bigner SH, Davidson N, Baylin S, Devilee P, Glover T, Collins FS, Weston A, Modali R, Harris CC, Vogelstein B (1989) Mutations in the p53 gene occur in diverse human tumour types. Nature 342:705–708
Sambrook J, Fritsch E, Maniatis T (1989) Molecular cloning: a laboratory manual. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY
Schutte J, Opalka B, Becher R, Bardenheuer W, Szymanski S, Lux A, Seeber S (1993) Analysis of the p53 gene in patients with isochromosome 17q and Ph1-positive or negative myeloid leukemia. Leuk Res 17:533–539
Serra A, Guerrasio A, Gaidano G, Rosso C, Rege-Cambrin G, Petroni D, Mazza U, Saglio G (1993) Molecular defects associated with the acute phase CML. Leuk Lymphoma 11:25–28
Shtivelman E, Gale RP, Dreazen O, Berribi A, Zaizov R, Kubonishi I, Miyoshi I, Canaani E (1987) bcr-abl RNA in patients with chronic myelogenous leukemia. Blood 69:971–973
Slingerland JM, Minden MD, Benchimol S (1991) Mutation of the p53 gene in human acute myelogenous leukemia. Blood 77:1500–1507
Soussi T, Jonveaux P (1991) p53 Alterations in human hematological malignancies: a review. Nouv Rev Fr Hematol 33:477–480
Urbano-Ispizua A, Cervantes F, Matutes E, Villamor N, Pujades A, Sierra J, Feliu E, Vives Corrons JL, Montserrat E, Rozman C (1993) Immunophenotypic characteristics of blast crisis of chronic myeloid leukaemia: correlations with clinicobiological features and survival. Leukemia 7:1349–1354
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Rovira, A., Urbano-Ispizua, A., Cervantes, F. et al. P53 Tumor suppressor gene in chronic myelogenous leukemia: A sequential study. Ann Hematol 70, 129–133 (1995). https://doi.org/10.1007/BF01682032
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DOI: https://doi.org/10.1007/BF01682032