By using the positional cloning approach we propose to identify and characterize the genes that are involved in the initiation and progression of B-CLL. We will focus on region 13q14, that is often involved in loss of heterozygosity (LOH) in B-CLL and on region 11q23 that is involved in loss of heterozygosity in B-CLLs that have progressed to a much more aggressive phenotype. By carrying out loss of heterozygosity studies at 13q14 we have identified the minimal region of loss that is involved in the majority of B-CLLs. We propose to clone and characterize the gene within this region that is mutated or deleted in the majority of B-CLLs. For this purpose we have sequenced the entire region of 550kb and we are in the process of investigating this region for the presence of transcribed genes that are mutated and/or deleted in CLL. Recently we have discovered mutations of the ATM gene in B CLLs, that have progressed to a much more aggressive phenotype. We propose to define the role of the ATM gene in the progression of B-CLL.
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