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High incidence of point mutations of p53 suppressor oncogene in patients with myelodysplastic syndrome among atomic-bomb survivors: a 10-year follow-up

Leukemia volume 16, pages 154–156 (2002)Cite this article

Myelodysplastic syndrome (MDS) is a group of clonal proliferative disorders of the bone marrow characterized by dyshematopoiesis and peripheral blood cytopenias.1 MDS is a preleukemic state, and approximately 40% of patients with MDS develop leukemia. The p53 gene, which is frequently mutated in a variety of malignant neoplasms including colon, lung, breast and liver carcinomas,2 has been shown to function as a tumor-suppressor gene. For hematologic malignancies, alterations of the p53 gene are found in blast cells of patients with chronic myelogenous leukemia in blast crisis, in acute myelogenous leukemia and in MDS.3 MDS provide an excellent model to reveal the mechanism of leukemogenesis.

These findings prompted us to study a possible role for p53 in the development or progression of MDS, and we studied p53 mutations in the highly conserved regions in 23 patients with MDS, including five atomic bomb survivors. Bone marrow samples from 23 patients, eight with refractory anemia (RA), 11 with RA with excess of blasts (RAEB), two with RAEB in transformation (RAEB in T) and two with chronic myelomonocytic leukemia (CMMoL) were collected between 1988 and 1992. Bone marrow mononuclear cells (BMMC) were isolated by a density gradient technique (Ficoll-sodium metrizoate d = 1.077 g/cm3). They then were washed twice with phosphate-buffered saline (PBS) and resuspended in the same medium. Subsequently the cells were used for either flow cytometric analysis or DNA analysis as described previously.4 High molecular weight DNA was prepared from BMMC of a patient with MDS. A DNA sample from a normal person was used as a control. Cells were incubated overnight at 37°C in sodium dodecyl sulfate and proteinase K. This was followed by phenol/chloroform extraction and ethanol precipitation, as described previously.4 Oligonucleotide primers for polymerase chain reaction (PCR) amplification and DNA sequencing were manufactured on an Applied Biosystems (ABI, Foster City, CA, USA) 394 DNA synthesizer and purified by denaturing polyacrylamide gel electrophoresis, and passage through a NEN-sorb column (DuPont, Boston, MA, USA). The names and nucleotide sequences of the primer pairs used in this work are as follows: SSCP primers: exon 5 sense 5′-TGT TCA CTT GTG CCC TGACT3′, antisense 5′-CAG CCC TGT CGT CTC TCC AG-3′, exon 6 sense 5′-CCC AGG CCT CTG ATT CCT CA-3′, antisense 5′-CAA CCA CCC TTA ACC CCT CC-3′. exon 7 sense 5′-ACG GGC CTC ATC TTG GGC CT-3′, antisense 5′-TGT GCA GGG TGG CAA GTG GC-3′, exon 8 sense 5′-TCC TTA CTG CCT CTT GCT TC-3′, antisense 5′-TCT CCT CCA CCG CTT CTT GT-3′, exon 9 sense 5′-ACT AAG CGA GGT AAG CAA GC-3′, antisense 5′-CTG GAA ACT TTC CAC TTG AT-3′. Sequence primers: exon 5 sense 5′-TGT TCA CTT GTG CCC TGA CT-3′, antisense 5′-CAG CCC TGT CGT CTC TCC AG-3′, exon 6 sense 5′-GCC TCT GAT TCC TCA CTG AT-3′, antisense 5′-TTA ACC CCT CCT CCC AGA GA-3′. exon 7 sense 5′-ACG GGC CTC ATC TTG GGC CT-3′, antisense 5′-TGT GCA GGG TGG CAA GTG GC-3′, exon 8 sense 5′-TAA ATG GGA CAG GTA GGA CC-3′, antisense 5′-TCC ACC GCT TCT TGT CCT GC-3′, exon 9 sense 5′-ACT AAG CGA GGT AAG CAA GC-3′, antisense 5′-CTG GAA ACT TTC CAC TTG AT-3′.

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Acknowledgements

This work was supported in part by an International Scientific Research Program Grants from the Ministry of Education and Culture in Japan. The authors wish to thank Ms K Yamamoto for typing this manuscript.

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  1. Department of Hematology and Oncology, Division of Clinical Research, Research Institute for Radiation Biology and Medicine, Hiroshima, Japan

    N Imamura

  2. Health Examination Center, Chugoku Rosai General Hospital, Hiroshima, Japan

    K Abe

  3. Department of Cancer Cytogenetics, Division of Molecular Biology Hiroshima University, Minami-ku, Hiroshima, Japan

    N Oguma

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Imamura, N., Abe, K. & Oguma, N. High incidence of point mutations of p53 suppressor oncogene in patients with myelodysplastic syndrome among atomic-bomb survivors: a 10-year follow-up. Leukemia 16, 154–156 (2002). https://doi.org/10.1038/sj.leu.2402277

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