Mutation analysis of the DNA-damage checkpoint gene CHK2 in myelodysplastic syndromes and acute myeloid leukemias

• Published in: Leukemia research Vol. 25; no. 4; pp. 333 - 338
• Main Authors: Hofmann, Wolf-K., Miller, Carl W., Tsukasaki, Kunihiro, Tavor, Sigal, Ikezoe, Takayuki, Hoelzer, Dieter, Takeuchi, Seisho, Koeffler, H.Phillip
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01-04-2001; Elsevier Science
• Subjects: Acute Disease; Acute myeloid leukemia; Amino Acid Substitution; Biological and medical sciences; Bone Marrow - pathology; CDS1; Checkpoint Kinase 2; CHK2; DNA Mutational Analysis; Female; Genes, cdc; Hematologic and hematopoietic diseases; Humans; Karyotyping; Leukemia, Myeloid - etiology; Leukemia, Myeloid - genetics; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Male; Medical sciences; Myelodysplastic syndrome; Myelodysplastic Syndromes - etiology; Myelodysplastic Syndromes - genetics; Point Mutation; Polymorphism, Genetic; Protein Kinases - genetics; Protein-Serine-Threonine Kinases; RAD53; CDS1; gDNA, genomic DNA; RARS, RA with ringed sideroblasts; FAB, French-American-British Cooperative Group; RA, refractory anemia; AML, acute myeloid leukemia; MDS, myelodysplastic syndrome; Myelodysplastic syndrome; RAEB-T, RAEB in transformation; CMML, chronic myelomonocytic leukemia; SSCP, single strand conformation polymorphism; RAD53; CHK2; RAEB, RA with excess of blasts; PCR, polymerase chain reaction; Acute myeloid leukemia; Human; Acute; Cell cycle; Genetics; Malignant hemopathy; Mutation; Tumor suppressor gene; Acute myelocytic leukemia
• ISSN: 0145-2126; 1873-5835
• DOI: 10.1016/S0145-2126(00)00130-2

Checkpoint genes code for a family of proteins which sense DNA damage in eukaryotic cells. They play an important role in the control of the cell cycle. The human CHK2 is a homolog of the yeast G
2 checkpoint kinases known as CDS1 and RAD53. The CHK2 may be a tumor suppressor gene because it was found to be mutated in some individuals with the Li–Fraumeni syndrome. These cases had a normal, non-mutated p53 gene. We performed a mutational analysis of the CHK2 gene using polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) in 41 bone marrow samples from individuals with myelodysplastic syndrome (MDS) and 41 samples of acute myeloid leukemias (AML). We found a novel G to C transversion resulting in a change from Ala to Gly at codon 507 of CHK2 in one MDS sample, but normal cells from this individual did not have the abnormality. In addition, we demonstrated a previously described polymorphism at codon 84 (A to G at nucleotide 252) of exon 1 of CHK2 in three of 41 MDS and three of 41 AML patients. The presence of a CHK2 mutation in MDS highlights the importance of alterations of cell cycle checkpoint genes in this disease.