A complex MLL rearrangement identified five years after initial MDS diagnosis results in out-of-frame fusions without progression to acute leukemia.

Chromosomal rearrangements of the MLL gene are uncommon in myelodysplastic syndromes (MDSs), and few studies of their molecular structures and oncogenic mechanisms exist. Here, we present a case of de novo MDS with a normal karyotype at initial diagnosis and a mild clinical course. Five years after the initial diagnosis, investigators identified a complex rearrangement of the MLL gene without progression to acute leukemia. The 5' part of the MLL gene is fused out of frame with the LOC100131626 gene, and the 3' part of the MLL gene out of frame with the TCF12 gene. Rapid amplification of complementary DNA 3' ends yielded two main fusion transcripts, which is in concordance with the two described isoforms of the LOC100131626 gene. For both isoform-fusion transcripts, the open reading frame terminates shortly after the breakpoint that is predicted to form two de facto truncated MLL proteins and disrupts the open reading frame of the LOC100131626, TCF12, and UBE4A genes. Neither dimerization nor a transcriptional activation domain, each of which is causally linked to MLL protein-mediated transformation, is present. This and other unusual MLL rearrangements probably represent a subclass of MLL gene abnormalities that have intrinsically no ability or only a weak ability to transform hematopoeitic cells and are identified only in the context of other hematopoetic malignancies.

A MLL-KIAA0284 fusion gene in a patient with secondary acute myeloid leukemia and t(11;14)(q23;q32).

MLL aberrations are found in approximately 10% of acute leukemias. More than 80 different MLL fusion genes have been cytogenetically described but a significant number of MLL fusion partners remain unidentified on the molecular level. We describe here the case of a patient who developed secondary acute myeloid leukemia five years after the patient had received adjuvant radiochemotherapy because of breast cancer. This therapy comprised 4 cycles epirubicin/cyclophosphamide, a mitoxantrone-based high-dose chemotherapy with autologous stem cell transplantation and a subsequent radiation. Cytogenetic bone marrow analysis revealed a translocation t(11;14)(q23;q32), with a MLL split signal in FISH analysis. By applying a long-distance inverse PCR method the KIAA0284 gene was identified as translocation partner. Both breakpoints, on chromosomes 11 and 14, were characterized. The breakpoint in the KIAA0284 gene was located 5' of the putative start codon and an in-frame MLL-KIAA0284 transcript was detectable by RT-PCR. The KIAA0284 gene has hitherto not been implicated in hematologic diseases and has never been reported as a translocation partner. Its physiological function is unknown. The expression of KIAA0284 in various tissues and hematologic diseases was investigated by real time quantitative PCR and turned out to be very low in all lymphatic and myeloid diseases investigated.

Life-long vitamin C supplementation in combination with cold exposure does not affect oxidative damage or lifespan in mice, but decreases expression of antioxidant protection genes.

Oxidative stress is suggested to be central to the ageing process, with endogenous antioxidant defence and repair mechanisms in place to minimize damage. Theoretically, supplementation with exogenous antioxidants might support the endogenous antioxidant system, thereby reducing oxidative damage, ageing-related functional decline and prolonging life- and health-span. Yet supplementation trials with antioxidants in animal models have had minimal success. Human epidemiological data are similarly unimpressive, leading some to question whether vitamin C, for example, might have pro-oxidant properties in vivo. We supplemented cold exposed (7+/-2 degrees C) female C57BL/6 mice over their lifespan with vitamin C (ascorbyl-2-polyphosphate), widely advocated and self administered to reduce oxidative stress, retard ageing and increase healthy lifespan. No effect on mean or maximum lifespan following vitamin C treatment or any significant impact on body mass, or on parameters of energy metabolism was observed. Moreover, no differences in hepatocyte and lymphocyte DNA oxidative damage or hepatic lipid peroxidation was seen between supplemented and control mice. Using a DNA macroarray specific for oxidative stress-related genes, we found that after 18 months of supplementation, mice exhibited a significantly reduced expression of several genes in the liver linked to free-radical scavenging, including Mn-superoxide dismutase. We confirmed these effects by Northern blotting and found additional down-regulation of glutathione peroxidase (not present on macroarray) in the vitamin C treated group. We suggest that high dietary doses of vitamin C are ineffective at prolonging lifespan in mice because any positive benefits derived as an antioxidant are offset by compensatory reductions in endogenous protection mechanisms, leading to no net reduction in accumulated oxidative damage.