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The MLL gene, at 11q23, undergoes chromosomal translocation with a large number of partner genes in both acute lymphoblastic and acute myeloid leukemia (AML). We report a novel t(9;11;19)(p22;q23;p13.3) disrupting MLL in an infant AML patient. The 5' end of MLL fused to chromosome 9 sequences on the der(11), whereas the 3' end was translocated to chromosome 19. We developed long-distance inverse-polymerase chain reaction assays to investigate the localization of the breakpoints on der(11) and der(19). We found that intron 5 of MLL was fused to intron 5 of MLLT3 at the der(11) genomic breakpoint, resulting in a novel in-frame MLL exon 5-MLLT3 exon 6 fusion transcript. On the der(19), a novel gene annotated as FLJ10374 was disrupted by the breakpoint. Using reverse transcription-polymerase chain reaction analysis, we showed that FLJ10374 is ubiquitously expressed in human cells. Transfection of the FLJ10374 protein in different cell lines revealed that it localized exclusively to the nucleus. In serum-starved NIH-3T3 cells, the expression of FLJ10374 decreased the rate of the G1-to-S transition of the cell cycle, whereas the suppression of FLJ10374 through short interfering RNA increased cell proliferation. These results indicate that FLJ10374 negatively regulates cell cycle progression and proliferation. Thus, a single chromosomal rearrangement resulting in formation of the MLL-MLLT3 fusion gene and haplo-insufficiency of FLJ10374 may have cooperated to promote leukemogenesis in AML with t(9;11;19).

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Introduction Coronary artery disease (CAD) is a dynamic inflammatory disease caused by atherosclerosis. GWAS showed that ZNF259 rs964184 encoding zinc finger protein (ZPR1) was associated with dyslipidemia and CAD. Recent research found that ZPR1 transcription is up-regulated in the brain of mice fed a high-fat diet, influencing the cell cycle, apoptosis, and RNA metabolism in neurons. This process at the heart vessels may increase oxidative stress and CAD. Purpose Study the association between the ZNF259 rs964184 C>G polymorphism with dyslipidemia and CAD susceptibility in a Portuguese population. Methods A case-control study was performed with 3,160 individuals, namely 1,723 CAD patients (mean age 53.3±7.9; 78.7% male) and 1,437 controls (mean age 52.8±7.8; 76.3% male). Participants were stratified into two age groups (<45 and >55 years). ZNF259 rs964184 C>G was genotyped and analysed using the dominant model (CG+GG vs CC). Multivariate logistic regression was performed in both age groups to investigate whether rs964184 polymorphism was associated with dyslipidemia and CAD susceptibility. Results The dominant model of ZNF259 was associated with dyslipidemia (OR=1.85; 95% CI: 1.22–2.79; p=0.003) and CAD (OR=1.46; 95% CI: 1.02–2.09; p=0.036) in the younger population under 45 years. In the >55 years group, this model was associated with dyslipidemia (OR 1.46; 95% CI: 1.06–2.01; p=0.020) but not with CAD. After multivariate logistic regression, the CG+GG remained an independent risk factor for CAD susceptibility only in the population <45 years (OR=1.60; 95% CI: 1.03–2.50; p=0.037). Conclusion ZNF259 rs964184 is a risk factor for dyslipidemia in the whole population. Dyslipidemia may up-regulate ZPR1 transcription, enhancing the vulnerability of coronary endothelial cells to both oxidative stress and inflammatory response, increasing CAD susceptibility. This mechanism seems more relevant at the cellular level in young patients representing a possible prophylactic and therapeutic target, especially in this age group. Funding Acknowledgement Type of funding sources: Public hospital(s). Main funding source(s): SESARAM EPERAM

The inclusion of a genetic risk score (GRS) can modify the risk prediction of coronary artery disease (CAD), providing an advantage over the use of traditional models. The predictive value of the genetic information on the recurrence of major adverse cardiovascular events (MACE) remains controversial. A total of 33 genetic variants previously associated with CAD were genotyped in 1587 CAD patients from the GENEMACOR study. Of these, 18 variants presented an hazard ratio >1, so they were selected to construct a weighted GRS (wGRS). MACE discrimination and reclassification were evaluated by C-Statistic, Net Reclassification Index and Integrated Discrimination Improvement methodologies. After the addition of wGRS to traditional predictors, the C-index increased from 0.566 to 0.572 (p=0.0003). Subsequently, adding wGRS to traditional plus clinical risk factors, this model slightly improved from 0.620 to 0.622 but with statistical significance (p=0.004). NRI showed that 17.9% of the cohort was better reclassified when the primary model was associated with wGRS. The Kaplan-Meier estimator showed that, at 15-year follow-up, the group with a higher number of risk alleles had a significantly higher MACE occurrence (p=0.011). In CAD patients, wGRS improved MACE risk prediction, discrimination and reclassification over the conventional factors, providing better cost-effective therapeutic strategies.

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