Homologous recombination in embryonal stem cells has been used to produce a fusion oncogene, thereby mimicking chromosomal translocations that frequently result in formation of tumor-specific fusion oncogenes in human malignancies. AF9 sequences were fused into the mouse Mll gene so that expression of the Mll-AF9 fusion gene occurred from endogenous Mll transcription control elements, as in t(9;11) found in human leukemias. Chimeric mice carrying the fusion gene developed tumors, which were restricted to acute myeloid leukemias despite the widespread activity of the Mll promoter. Onset of perceptible disease was preceded by expansion of ES cell derivatives in peripheral blood. This novel use of homologous recombination formally proves that chromosomal translocations contribute to malignancy and provides a general strategy to create fusion oncogenes for studying their role in tumorigenesis.

The MLL gene from human chromosome 11q23 is involved in >30 different chromosomal translocations resulting in a plethora of different MLL fusion proteins. Each of these tends to associate with a specific leukaemia type, for example, MLL-AF9 is found mainly in acute myeloid leukaemia. We have studied the role of the Mll-AF9 gene fusion made in mouse embryonic stem cells by an homologous recombination knockin. Acute leukaemias developed in heterozygous mice carrying this fusion as well as in chimeric mice. As with human chromosomal translocation t(9;11), the majority of cases were acute myeloid leukaemias (AMLs) involving immature myeloblasts, but a minority were acute lymphoblastic leukaemia. The AMLs were preceded by effects on haematopoietic differentiation involving a myeloproliferation resulting in accumulation of Mac-1/Gr-1 double-positive mature myeloid cells in bone marrow as early as 6 days after birth. Therefore, non-malignant expansion of myeloid precursors is the first stage of Mll-AF9-mediated leukaemia followed by accumulation of malignant cells in bone marrow and other tissues. Thus, the late onset of overt tumours suggests that secondary tumorigenic mutations are necessary for malignancy associated with MLL-AF9 gene fusion and that myeloproliferation provides the pool of cells in which such events can occur.

We performed a genome-wide association study on 1,292 individuals with abdominal aortic aneurysms (AAAs) and 30,503 controls from Iceland and The Netherlands, with a follow-up of top markers in up to 3,267 individuals with AAAs and 7,451 controls. The A allele of rs7025486 on 9q33 was found to associate with AAA, with an odds ratio (OR) of 1.21 and P = 4.6 × 10−10. In tests for association with other vascular diseases, we found that rs7025486[A] is associated with early onset myocardial infarction (OR = 1.18, P = 3.1 × 10−5), peripheral arterial disease (OR = 1.14, P = 3.9 × 10−5) and pulmonary embolism (OR = 1.20, P = 0.00030), but not with intracranial aneurysm or ischemic stroke. No association was observed between rs7025486[A] and common risk factors for arterial and venous diseases—that is, smoking, lipid levels, obesity, type 2 diabetes and hypertension. Rs7025486 is located within DAB2IP, which encodes an inhibitor of cell growth and survival.

LPA sequence variants were associated with atherosclerotic burden, but not with primarily thrombotic phenotypes.

Phosphomannomutase 2 (PMM2-CDG) is the most common congenital disorder of N-glycosylation and is caused by a deficient PMM2 activity. The clinical presentation and the onset of PMM2-CDG vary among affected individuals ranging from a severe antenatal presentation with multisystem involvement to mild adulthood presentation limited to minor neurological involvement. Management of affected patients requires a multidisciplinary approach. In this article, a systematic review of the literature on PMM2-CDG was conducted by a group of international experts in different aspects of CDG. Our managment guidelines were initiated based on the available evidence-based data and experts' opinions. This guideline mainly addresses the clinical evaluation of each system/organ involved in PMM2-CDG, and the recommended management approach. It is the first systematic review of current practices in PMM2-CDG and the first guidelines aiming at establishing a practical approach to the recognition, diagnosis and management of PMM2-CDG patients.

Background and Purpose-The widespread use of aspirin requires clarification of the aspirin resistance phenomenon.Most studies on this field are focused on patients which may affect the action of aspirin. Methods-We evaluated the biological efficacy of aspirin in healthy subjects. Results-Agonist-induced platelet aggregation was fully abrogated by 100 mg of aspirin in all individuals. By contrast, with the platelet function analyzer-100 device, 33.3% of the subjects displayed no response. This failure was overcome by 500 mg or by in vitro treatment of blood with 30 mol/L acetylsalicylic acid. Intake of 100 mg of aspirin efficiently reduced by 75% the level of 11-dehydro thromboxane B 2 (11-dTxB 2 ) in all cases. However, variability on the pre-aspirin level (range 72.4 to 625.9 ng/mmol creatinine) led to substantial differences in the residual amount of the metabolite between subjects treated with aspirin (range 12.9 to 118.0 ng/mmol creatinine). Finally, there was no influence of platelet glycoprotein IIb/IIIa (Pro33Leu), platelet glycoprotein Ia/IIa, (C807T), and FXIII (Val34Leu) polymorphisms on the efficacy of aspirin. However, the cyclooxygenase (Cox)-1 50T allele associated with higher level of 11-dTxB 2 , both before and after aspirin. Moreover, the Cox-2 Ϫ765C variant displayed a slightly higher reduction in 11-dTxB 2 level on treatment with aspirin. Conclusions-Our findings suggest that full resistance of healthy subjects to aspirin is rather unlikely. However, differences in aspirin absorption, or pharmacokinetic, or other unrecognized factors may lead to lack of effect of low dose of aspirin in some subjects when using tests like platelet function analyzer-100. Whether Cox polymorphisms are thrombotic risk factor for patients under aspirin will require further research.

The prevalent with the t(4;11)(q21;q23), but cases of ANLL have also been described with this translocation. Further the t(11;19)(q23;pll) is seen in early B-ALL, common-ALL (c-ALL), ANLL, and occasionally in T-ALL. Other translocations, such as t(10;11)(p11-15;q23) and t(11;17)(q23;q21), are found in ANLL tumors that are otherwise indistinguishable from those discussed above.Recently, a gene on chromosome 11q23 designated MLL (also ALL-1 and HRX) (18-23) has been described that is rearranged in t(4;11) and t(11;19) (18-22, 24-27). These translocations have been studied at the molecular level (18,19,21), and the breakpoints create a fusion of the MLL gene with a gene called AF4 in the case of the t(4;11) (19) or ENL in t(11;19) (21). The MLL breakpoints seem restricted in both t(4;11) and t(11;19) around exon 7 and 8. No information on the comparable breaks in AF4 or ENL genes is yet available. In this paper we determine the breakpoint within MLL of several additional translocations [namely, t(1;11), t(6;11), t(9;11), t(10;11), t(11;17), t(11;22)], two different t(X;11), and two interstitial deletions of llq, as well as a panel of t(4;11) and t(11;19) patient samples. All major hematopoietic lineages are represented. Restricted breakpoints occur in MLL andAF4 and ENL, irrespective oftumor phenotype. Our data suggest that gene fusion of MLL occurs in multipotent hematopoietic precursor cells.MATERIALS AND METHODS DNA Analysis of Acute Leukemia Sampls: Fiter Hybridization. Ten microgrms of genomic DNA was digested with restriction enzyme, and the digestion products were separated on 0.8% agarose gels. The gels were blotted (28) onto nylon membranes and hybridized as described (28) with either the myeloid-lymphoid leukemia (MLL) genomic probe P4 (27) [containing exon 8, a 5' MLL probe (EX5/GEB13) which was prepared by reverse transcriptase (RT)-PCR from RS411 cDNA extending from residues 3869 to 4443 of the published MLL sequence (19,21], or a 3' MLL probe (VAR8F/EX11B), which was also prepared by RT-PCR from RS411 cDNA, extending from residues 4318 to the BamHI site, in exon 11, at residue 4609 of the published MLL sequence.

It has long been thought that an individual thrombotic tendency increases the risk of myocardial infarction, especially in young adults. Several “prothrombotic” genetic factors that may influence the individual thrombotic risk have been identified. To investigate the association between the risk of myocardial infarction at a young age and genetic factors thought to be associated with an increased tendency to thrombosis (the polymorphisms 4G/5G of the PAI-1 gene, PIA1/PIA2 of the platelet glycoprotein IIIa, C3550T of the platelet glycoprotein Ib gene, G10976A of the factor VII gene, C677T of the methylenetetrahydrofolate reductase gene, G1691A of the factor V gene, and G20210A of the prothrombin gene), we performed a case-control study evaluating 200 survivors (185 men, 15 women) of myocardial infarction who had experienced the event before the age of 45 years and 200 healthy subjects with a negative exercise test, individually matched for sex, age, and geographic origin with the cases. The presence of the PIA2 polymorphic allele was the only prothrombotic genetic factor associated with the risk of myocardial infarction at a young age. The odds ratio for carriers of the PIA2 allele compared with those of the PIA1 allele was 1.84 (95% confidence intervals (CI) 1.12 to 3.03). There was a significant interaction between the presence of the PIA2 allele and smoking: with their simultaneous presence, 46% (95% confidence intervals 11% to 81%) of premature myocardial infarctions were attributable to the interaction between the two factors. In conclusion, carrying the PIA2 polymorphic allele of platelet glycoprotein IIIa was the only genetic prothrombotic factor associated with the risk of developing myocardial infarction at a young age. The clinical expression of this genetic predisposition seems to be enhanced by smoking.