Molecular genetics of lymphoid malignancies

Abstract

Advances in molecular genetics during the last decade has made it possible to identify genetic lesions in malignant cells that are specific for disease entities with a common clinical presentation and prognosis. In chronic lymphocytic leukemia (CLL) deletions in 13ql4 are the most frequently occurring abnormalities and deletions cluster around marker D13S319 suggesting that a tumor suppressor gene is located in this region. Southern blot identifies deletions of D13S319 in more than 40% of CLL patients. Interphase FISH is equally efficient in detecting deletions and it also reveals that different subclones can occur with variable numbers of alleles in the D13S319 region.

Trisomy 12 is the most common cytogenetic abnormality in CLL, but it is still unknown how this abnormality contributes to disease development or progression. In a detailed FISH analysis of a case with a chromosome 12 abnormality we found amplification of the 12ql3-15 region. The MDM2 gene was found to be most frequently amplified, suggesting that genes in this region can provide a growth advantage for CLL cells.

Deletions of the long arm of chromosome 6 are frequently found in lymphoid malignancies. PCR analysis of loss of heterozygosity (LOH) revealed that deletions of 6q occur in 36% of acute lymphoblastic leukemia (ALL) cases, showing that this abnormality is more frequent than has been previously recognized. A minimal deleted region of 4 cM around marker D6S283 has been identified and our results suggest that this is the location of a tumor suppressor gene relevant for ALL. Our results also indicate that there is at least one more region on 6q that is commonly deleted in NHL that might contain a gene of interest for the development of high grade lymphomas. In B-CLL patients, deletions of 6q are found particularly in a subgroupt of patients with abberant, non-productive rearrangements of the genes for the B chain of the T-cell receptor. Abberrant TcR B gene rearrangement is a rare event in B-CLL occuring in 6% of patients. The reason for the connection between TcR B gene rearrangement and deletion of 6q is not clear. The BCL-2 protein, which can contribute to disease development and acquisition of resistance to drug therapy, is overexpressed in several different lymphoid malignancies including CLL. However, translocation of the BCL-2 gene seems to be a rare event occuring in 9% of the CLL cases. These results suggest that BCL-2 overexpression in CLL in most cases is caused by mechanism other than gene translocation.

Cytogenetic studies suggest the presence of a candidate gene relevant for development of hairy cell leukemia (HCL) at chromosome 5ql3.3. We have defined a YAC clone spanning the breakpoint and two cosmid clones on either side of the breakpoint. Using the cosmids for interphase FISH analysis in HCL patients we detect breakpoints in subclones of the malignant cells. The defined region is closely connected to a recently reported breakpoint region found in AML and MDS, suggesting that the candidate gene in HCL may be identical to a gene that is deleted in myeloid malignancies.