Genomic instability of microsatellite repeats and its association with the evolution of chronic myelogenous leukemia [see comments]

Abstract

Tumorigenesis has been shown to proceed through a series of genetic alterations involving protooncogenes and tumor-suppressor genes. Investigation of genomic instability of microsatellites has indicated a new mechanism for human carcinogenesis in hereditary nonpolyposis colorectal cancer and sporadic cancer and this instability has been shown to be related to inherited predisposition to cancer. This study was conducted to determine whether such microsatellite instability is associated with the evolution of chronic myelogenous leukemia (CML) to the blast crisis. Nineteen CML patients clinically progressing from the chronic phase to accelerated phase or blast crisis and 20 other patients in the CML chronic phase were studied. By polymerase chain reaction assay, DNAs for genomic instability in five separate microsatellites in chromosome arms 5q (Mfd27), 17p (Mfd41), 18q (DCC), 3p (CI3–9), and 8p (LPL) were examined. Differences in unrelated microsatellites of chronic and blastic phase DNAs in 14 of 19 patients (73.7%) were demonstrated. Somatic instability in five microsatellites, Mfd27, Mfd41, DCC, CI3–9, and LPL, was detected in 2 of 19 (10.5%), 8 of 19 (42.1%), 11 of 19 (57.9%), 4 of 17 (23.5%), and 4 of 17 (23.5%) cases. In 10 of 19 cases (52.6%), genetic instability in at least two of five microsatellites was observed and was categorized as replication error (RER+) phenotype. CML evolution cases with myeloid, lymphoid, and mixed phenotypes and the blast crisis and accelerated phase showed somatic instability in a number of microsatellites. No alterations in leukemic cells at the chronic phase could be detected in any microsatellites. These data indicate instability of microsatellites (RER+) but not familial predisposition to possibly be a late genetic event in the evolution of CML to blast crisis. In the microsatellite of the DCC gene, complicated alterations in band patterns caused by instability as well as loss of heterozygosity (LOH) were observed in 13 of 19 cases (68.4%): instability in 9 cases, instability plus LOH in 2 cases, and only LOH in 2 cases. These highly frequent alterations in microsatellites, including instability and LOH, suggesting that secondary events due possibly to loss of fidelity in replication and repair machinery may be significantly associated with CML evolution.

Microsatellite instability during the progression of acute myelocytic leukaemia

“…Recent studies support the notion that the lack of mismatch repair increases mutagenesis and leads to tumour progression (Bicknell et al, 1994;Lazer et al, 1994). In accordance with these studies, in some types of neoplasms a higher incidence of MSI was observed in more advanced stages of malignancy (Chong et al, 1994;Han et al, 1993;Wada et al, 1994). To determine if MSI might play an important role in the progression of AML, we analysed MSI in AML at diagnosis, remission, and relapsed stages for each of 17 individuals.…”

“…Recent studies of MSI during cancer development have found that in some tissue types MSI predominates in poorly differentiated and advanced tumours (Chong et al, 1994;Han et al, 1993;Lothe et al, 1993). Wada et al (1994) reported a high frequency (53%) of MSI in the DNA of blast phase leukaemic cells from patients with chronic myelocytic leukaemia (CML), and concluded that the development of MSI was a late genetic event in the evolution of CML to blastic crisis. This loss of fidelity in replication and repair mechanisms may indeed contribute to the progression of a more malignant disease, and may not merely be a sign of progression.…”

How animal models of leukaemias have already benefited patients

“…Chronic myelogenous leukaemia is due to the Philadelphia chromosome, encoding the Bcr/Abl fusion. Careful epidemiological modelling has revealed that it can be explained by a single mutation model (Michor et al, 2006), despite the fact that its genome is quite unstable and that other genetic abnormalities are frequently observed, particularly when the disease progresses towards acute phase (Wada et al, 1994). This relative low number of driving abnormalities holds true for most translocation-associated leukaemias.…”

Microsatellite analysis of childhood leukemia: Correlation of 9p and 12p chromosome abnormalities with expression of related genes

“…Loci and the primer sequences for microsatellite analysis in this study were shown in Table 2 and have been described previously. [17][18][19] The locus D9S171 on 9p and two loci (D12S89 and D12S98, which flank the TEL gene) on 12p were selected because of a relatively high frequency of LOH in these loci in childhood hematologic malignancies. The polymerase chain reaction (PCR) for amplifying each region was performed on 0.2 µg DNA template in a total volume of 50 µL, containing 2 µmol/L each primer, 200 µmol/L dNTP, 10 mmol/L Tris-HCl (pH 8.3), 50 mmol/L KCl, 1.5 mmol/L MgCl 2 and 1.25 U Taq DNA polymerase (Perkin-Elmer Cetus).…”