Diagnostic tool for the identification of MLL rearrangements including unknown partner genes.

Approximately 50 different chromosomal translocations of the human MLL gene are currently known and associated with high-risk acute leukemia. The large number of different MLL translocation partner genes makes a precise diagnosis a demanding task. After their cytogenetic identification, only the most common MLL translocations are investigated by RT-PCR analyses, whereas infrequent or unknown MLL translocations are excluded from further analyses. Therefore, we aimed at establishing a method that enables the detection of any MLL rearrangement by using genomic DNA isolated from patient biopsy material. This goal was achieved by establishing a universal long-distance inverse-PCR approach that allows the identification of any kind of MLL rearrangement if located within the breakpoint cluster region. This method was applied to biopsy material derived from 40 leukemia patients known to carry MLL abnormalities. Thirty-six patients carried known MLL fusions (34 with der(11) and 2 with reciprocal alleles), whereas 3 patients were found to carry novel MLL fusions to ACACA, SELB, and SMAP1, respectively. One patient carried a genomic fusion between MLL and TIRAP, resulting from an interstitial deletion. Because of this interstitial deletion, portions of the MLL and TIRAP genes were deleted, together with 123 genes located within the 13-Mbp interval between both chromosomal loci. Therefore, this previously undescribed diagnostic tool has been proven successful for analyzing any MLL rearrangement including previously unrecognized partner genes. Furthermore, the determined patient-specific fusion sequences are useful for minimal residual disease monitoring of MLL associated acute leukemias.

C825T polymorphism in the human G protein beta 3 subunit gene and preeclampsia; a case control study.

OBJECTIVE: Recently, a polymorphism of the gene encoding for the G protein beta3-subunit (GNB3) has been described. The T allele of this polymorphism (825T) is associated with endothelium dysfunction. Endothelium dysfunction has been described in women with preeclampsia. We, therefore, tested the hypothesis that in women who have had preeclampsia the T allele is more prevalent than in controls. STUDY DESIGN: We conducted a case-control study of 157 women with preeclampsia during 1991-1996. Cases and controls were tested for the presence of 825T by genotyping. Logistic regression methods were used for data analysis. RESULTS: The frequency of the T allele of the GNB3 gene was similar in cases (0.30) and controls (0.27) (odds ratio 1.24, 95% confidence interval 0.88-1.75). Compared to controls, we found a high frequency of the T allele in patients with the hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome (odds ratio 4.25, 95% confidence interval 1.12-16.05). CONCLUSION: The frequency of the T allele of the GNB3 gene, which serves as a marker for endothelium dysfunction, was not different between women with preeclampsia and controls. Women with the HELLP syndrome had a high frequency of the T allele. This suggests that this polymorphism in the GNB3 gene does not contribute to endothelium dysfunction in women with preeclampsia while it does contribute in women with the HELLP syndrome.

Acute lymphoblastic leukemia followed by a clonally-unrelated EBV-positive non-Hodgkin lymphoma and a clonally-related myelomonocytic leukemia cutis.

BACKGROUND: Complicating malignant hematopoietic proliferations might severely hamper the course of acute lymphoblastic leukemia (ALL) in patients with an otherwise good prognosis. It is important to distinguish whether such neoplastic proliferations represent ALL relapses or secondary treatment-related malignancies. PROCEDURE: We present an 11-year-old girl with precursor-B-ALL in whom maintenance treatment was complicated by an isolated ALL relapse in the brain, nodular lymphoproliferations in the liver, and an isolated myelo-monocytic leukemia cutis. All these hemato-oncologic malignancies occurred in the background of a secondary immunodeficiency, most likely caused by cytotoxic treatment. RESULTS AND CONCLUSIONS: Using a stepwise molecular approach, we were able to demonstrate that the liver infiltrates were Epstein-Barr virus (EBV)-positive, contained monoclonal mature B-cells with immunoglobulin heavy chain gene (IGH) gene rearrangements unrelated to the primary ALL, and thus represented a true secondary non-Hodgkin lymphoma (NHL). In contrast, the skin infiltrates consisted of myelo-monocytic cells with clonal IGH and T-cell receptor gamma gene rearrangements, identical to the precursor-B-ALL blasts at diagnosis. Thus, the disease course of the precursor-B-ALL patient was complicated by two different isolated extramedullary relapses (brain and skin) and a secondary EBV(+) B-NHL.