Analysis of candidate molecular targets in adult (CML) and childhood (AML, ALL) Leukemias

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Bilkent University
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Candidate molecular targets were investigated in three different types of leukemias, chronic myeloid leukemia (CML), acute myeloid leukemia (AML) and acute lymphocytic leukemia (ALL). The first group of these molecular targets was identified through a cDNA based gene expression profile analysis in sixty-seven CML patients who were classified according to clinical parameters known as new prognostic score (NPS). CML patients can be divided into three groups of low-risk, intermediate-risk, and high-risk, based on NPS. Response of these risk groups to treatment is not uniform and the gene expression profiles associated with each risk group remain unknown. Seven genes were chosen from a cDNA microarray study in which two high versus two low-risk patients were analyzed. Semi-quantitative and real-time reverse transcription polymerase chain reaction (RT-PCR) analysis of these differentially expressed transcripts highly correlated with the microarray data. Expression levels of all genes, except PTGS1, were significantly different between the high (n=9) and low-risk (n=7) CML by semi-quantitative RT-PCR (IFITM1 and CXCL3 p=0.001; CCNH p=0.012; RAB1A p=0.01, PRKAR2B p=0.016; UCP2 p=0.04; and PTGS1 p=0.315). Real-time RT-PCR analysis showed similar results for IFITM1 expression in thirty-four low and eleven high-risk patients (p=9.7976 x 10-11). Higher IFITM1 or lower CXCL3 expression correlated with improved survival (p=0.01 and p=0.059 respectively). Gene expression profiling is a valuable tool to identify candidate risk group indicator genes for the development of a molecular classification system for CML, which may also predict survival. Although the connection between DNA-repair gene mutations and hematological malignancies are now well established, germ-line mutations in the base excision repair (BER) pathway was only recently documented in an inherited cancer syndrome in human homologue of E. coli mut Y (MYH). Interestingly, the cancer associated MYH missense mutations Tyr165Cys and Gly382Asp have been documented with a high frequency (1 percent) in a control group of the British population. Therefore, we screened the above mentioned missense variants in two different childhood leukemias, AML (n=45) and ALL (n=140). Neither mutation was present in any of the patient samples and controls, except for one patient diagnosed with AML/M3. Tyr165Cys mutation in the heterozygous state was present in the sample obtained at the time of initial diagnosis. Further sampling, at remission, and the analysis of parental DNA, showed only the normal allele. Therefore, the mutation was considered to be specific for the leukemic blasts. Based on these results, an association between childhood leukemias and the MYH missense variants Tyr165Cys and Gly382Asp was not observed. Also, these variants appear to be absent -if not at a very low frequency- in the Turkish population, contrary to the British population.

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