Molecular genetics of lymphoid malignancies

A b s t r a c t MOLECULAR GENETICS OF LYMPHOID MALIGNANCIES Mats Merup, MD Department of Medicine, Karolinska Institute at Huddinge Hospital, 141 86 Huddinge and Radiumhemmet, Karolinska Hospital, 171 76 Stockholm, Sweden. 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. ISBN 91-628-2450-

X-bunden trombocytopeni med talassemi i två svenska familjer : Överväg hereditära orsaker till trombocytopeni och benmärgsfibros

[X-linked thrombocytopenia with thalassemia in two families in Sweden. Consider hereditary causes of thrombocytopenia and bone marrow fibrosis] (Engelsk titel)</p

Different outcome of allogeneic transplantation in myelofibrosis using conventional or reduced-intensity conditioning regimens

Allogeneic haematopoietic stem cell transplantation remains the only curative treatment of myelofibrosis with myeloid metaplasia (MMM). Previous reports have indicated significant treatment-related mortality (TRM) for patients transplanted after myeloablative conditioning but superior survival has been reported after reduced-intensity conditioning (RIC). We report the results of a survey of all allogeneic transplantations for MMM performed in Sweden at six transplant units between 1982 and 2004. Twenty-seven patients were transplanted; 17 with a myeloablative conditioning regimen and 10 with RIC. The median age was 50 years (5-63 years) at transplantation. After a median follow up of 55 months, 20 patients are alive. TRM was 10% in the RIC group and 30% in the myeloablative group. There was no difference in survival for high or low-risk patients according to Cervantes score or between sibling and unrelated donor transplantations

The GNAS1 T393C polymorphism and lack of clinical prognostic value in chronic lymphocytic leukemia

Chronic lymphocytic leukemia (CLL) is a clinically heterogeneous disease with no known single predisposing genetic factor shown in all cases. Recently, a single nucleotide polymorphism (SNP) T393C in the GNAS1 gene has been reported to have a clinical impact on CLL progression and overall survival. In order to further investigate the T393C SNP in CLL, we have genotyped 279 CLL cases and correlated the genotypes to clinical outcome and other known prognostic factors such as the immunoglobulin heavy chain variable (IGHV) gene mutation status and CD38 expression. In the present study, no difference in overall survival or time to treatment was observed in the CLL patients with the different genotypes in contrast to the previous report. Furthermore, no correlation was observed with the T393C genotypes and IGHV mutational status, Binet stage or CD38 in this cohort. In summary, our data does not support the use of the T393C GNAS SNP as a clinical prognostic factor in CLL

Disruption of a novel Ectodermal Neural Cortex 1 antisense gene, ENC- 1AS and identification of ENC-1 overexpression in hairy cell leukemia

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