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The discovery of underlying genetic lesions helps to better understand the mechanisms of leukemogenesis and identify prognostic subgroups. Recent insights have allowed normal karyotype acute myeloid leukemia (AML) to be split into many molecular entities according to the genetic status of FLT3, NPM, CEBPA and MLL. Genome-wide single nucleotide polymorphism analysis was performed on 22 well-characterised AML patients with a normal karyotype. At the same time, microsatellite instability was investigated using a commonly used panel of polymorphic markers. Loss of heterozygosity (LOH) was found in 22.7% of cases without an associated copy number variation, suggesting that LOH represented an acquired partial uniparental disomy (aUPD) event. Three UPD+ cases harboured NPM mutations, associated with FLT3-ITD in two of them. An additional UPD patient had mutations both in CEBPA and in WT1. MSI was present at three loci in the three UPD+ cases (60%), whereas single locus MSI was present in three UPD- patients (17%). MSI involved the polymorphic PIG3 promoter in two UPD+ cases. It remains to be tested whether UPD and MSI association marks a common pathway of leukemogenesis. [ABSTRACT FROM AUTHOR]

Acute myeloid leukemia (AML) is a heterogeneous group of disorders characterized by abnormal proliferation of myeloid precursors and a maturation block. Underlying genetic lesions determine an altered expression program (transcriptosome) that can be studied in depth by massive technologies. Alternatively, we selected a pathway profiling strategy based on the current knowledge in order to stratify de novo AML patients and identify those cases which would potentially benefit from the use of new chemotherapeutic agents. One hundred and thirty-two RNA samples obtained from de novo adult AML patients were tested for FLT3, FLT3-LG, NDST1, HDAC2, ATRX, FOS, DNMT1, DNMT3A, DNMT3B, NBS1, RAD50, MRE11A, Meis1 and Meis2 expression using quantitative PCR (qPCR) assays. Clinical and biologic findings were correlated with expression results. Cluster analysis was also performed. FLT3 expression defined three subgroups of patients. The best outcome was found in the group with the lowest FLT3 expression. Intermediate levels of FLT3 were associated with the worst outcome. Patients with low levels of ATRX more frequently presented an adverse karyotype whereas cases with preserved ATRX levels showed an excellent outcome. In accordance with previous results, Meis1 downregulation is a useful surrogate marker indicating a good prognosis in AML patients. Simple qPCR platforms may help to identify different biologic subgroups in AML. Copyright © 2006 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

To investigate the biologic relevance of microsatellite instability (MSI) in de novo acute myeloid leukemia (AML), 102 consecutive adult patients were analyzed by using a panel of seven microsatellites (BAT25, BAT26, D13S1267, D13S174, D2S123, D5S346 and Mdf15). Frame-shift mutations in the repetitive sequences in the coding region of MSH3, MSH6, BAX, TGFBRII and IGFRII were also investigated by using a fluorescent PCR-based assay. Methylation-specific PCR was used to determine the methylation status of hMLH1 in MSI+ cases. MSH3, MSH6 and MLH1 expression was also analyzed in 68 cases by means of real-time quantitative PCR. MSI was detected in 20 cases: 14 cases had MSI-high (instability of at least two microsatellite markers) and 6 cases corresponded to MSI-low (a single polymorphic marker with instability). Six MSI+ cases showed an associated MLL rearrangement (p=0.002). No single case showed a mutation in the repetitive sequences of the MSH3, MSH6, BAX, TGFBRII and IGFRII genes. Most samples displayed low mRNA levels of the repair genes. hMLH1 promoter was hypermethylated in five MSI+ cases. Overall survival analysis revealed no adverse effect of MSI positivity. These results suggest that MSI may be a common biologic finding in de novo AML. [ABSTRACT FROM AUTHOR]