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Several recurring chromosomal translocations involve the AML1 gene at 21q22 in myeloid leukemias resulting in fusion mRNAs and chimeric proteins between AML1 and a gene on the partner chromosome. AML1 corresponds to CBFA2, one of the DNA-binding subunits of the enhancer core binding factor CBF. Other CBF DNA-binding subunits are CBFA1 and CBFA3, also known as AML3 and AML2. AML1, AML2 and AML3 are each characterized by a conserved domain at the amino end, the runt domain, that is necessary for DNA-binding and protein dimerization, and by a transactivation domain at the carboxyl end. AML1 was first identified as the gene located at the breakpoint junction of the 8;21 translocation associated with acute myeloid leukemia. The t(8;21)(q22;q22) interrupts AML1 after the runt homology domain, and fuses the 5' part of AML1 to almost all of ETO, the partner gene on chromosome 8. AML1 is an activator of several myeloid promoters; however, the chimeric AML1/ETO is a strong repressor of some AML1-dependent promoters. AML1 is also involved in the t(3;21)(q26;q22), that occurs in myeloid leukemias primarily following treatment with topoisomerase II inhibitors. We have studied five patients with a 3;21 translocation. In all cases, AML1 is interrupted after the runt domain, and is translocated to chromosome band 3q26. As a result of the t(3;21), AML1 is consistently fused to two separate genes located at 3q26. The two genes are EAP, which codes for the abundant ribosomal protein L22, and MDS1, which encodes a small polypeptide of unknown function. In one of our patients, a third gene EVI1 is also involved. EAP is the closest to the breakpoint junction with AML1, and EVI1 is the furthest away. The fusion of EAP to AML1 is not in frame, and leads to a protein that is terminated shortly after the fusion junction by introduction of a stop codon. The fusion of AML1 to MDS1 is in frame, and adds 127 codons to the interrupted AML1. Thus, in the five cases that we studied, the 3;21 translocation results in expression of two coexisting chimeric mRNAs which contain the identical runt domain at the 5' region, but differ in the 3' region. In addition, the chimeric transcript AML1/MDS1/EVI1 has also been detected in cells from one patient with the 3;21 translocation as well as in one of our patients. Several genes necessary for myeloid lineage differentiation contain the target sequence for AML1 in their regulatory regions. One of them is the CSF1R gene. We have compared the normal AML1 to AML1/MDS1, AML1/EAP and AML1/MDS1/EVI1 as transcriptional regulators of the CSF1R promoter. Our results indicate that AML1 can activate the promoter, and that the chimeric proteins compete with the normal AML1 and repress expression from the CSF1R promoter. AML1/MDS1 and AML1/EAP affect cell growth and phenotype when expressed in rat fibroblasts. However, the pattern of tumor growth of cells expressing the different chimeric genes in nude mice is different. We show that when either fusion gene is expressed, the cells lose contact inhibition and form foci over the monolayer. In addition, cells expressing AML1/MDS1 grow larger tumors in nude mice, whereas cells expressing only AML1/EAP do not form tumors, and cells expressing both chimeric genes induce tumors of intermediate size. Thus, although both chimeric genes have similar effects in transactivation assays of the CSF1R promoter, they affect cell growth differently in culture and have opposite effects as tumor promoters in vivo. Because of the results obtained with cells expressing one or both genes, we conclude that MDS1 seems to have tumorigenic properties, but that AML1/EAP seems to repress the oncogenic property of AML1/MDS1.

A nonrandom translocation between chromosomes 3 and 21, t(3;21)(q26.2;q22) has been detected in patients with a myelodysplastic syndrome or acute myeloid leukemia after treatment (t-MDS/t-AML) for a primary malignant disease and in chronic myelogenous leukemia in blast crisis (CML-BC). In these patients, the breakpoint on chromosome 21 is at band 21q22. This band is also involved in the t(8;21)(q22;q22) detected in 40% of the patients with acute myeloid leukemia subtype M2 (AML-M2) de novo who have an abnormal karyotype. In the t(8;21), the AML1 gene is the site of the breakpoint on chromosome 21. The AML1 gene is transcribed from telomere to centromere, and in the t(8;21) the 5' part of AML1 is fused to the ETO gene on chromosome 8 to produce the chimeric AML1/ETO on the der(8) chromosome. We found that AML1 is also rearranged in two t-AML patients and in one CML-BC patient with the t(3;21), but the breakpoints are approximately 40 to 60 kb downstream to those of AML-M2 patients. This region contains at least one additional exon of AML1, as determined by using an AML1 cDNA as a probe in Southern blot analysis. The t(3;21) breakpoints for the remaining patients could not be determined because, by fluorescence in situ hybridization analysis, the breaks are outside of the region covered by the available probes.

An additional case of leiomyosarcoma of spermatic cord which brings the total reported number to 49, is described. The case is compared with the others and further data on histogenesis and histological behaviour of the tumor, are given. Surgical treatment and role of radiotherapy and chemotherapy, are discussed.

Dynamic, ECG-gated, steady-state free precession short-axis images were obtained (GE Healthcare, 1.5T) in 8-12 slices in 15 patients with previous myocardial infarction. An expert cardiologist provided the reference values for: 1) left ventricular (LV) volumes and mass, by manually tracing endo and epicardial contours; 2) regional wall motion (WM) interpretation, by grading (normal, abnormal) three slices selected at apical, mid and basal level. Custom software based on image noise distribution and on image gradient was applied, from which end-diastolic (ED) and end-systolic (ES) volumes and mass were computed, as well as regional fractional area change (RFAC), from which automated classification of regional WM abnormality was defined. Comparison with reference values was performed by: 1) linear regression and Bland-Altman analyses for LV volumes and mass; 2) levels of agreement between the cardiologist WM grades and the automated classification. Optimal correlations (r2>;.97) and no bias were found for ED and ES volumes, while LV mass resulted in a good correlation (ED: r2 = .81; ES: r2 = .74) with a minimal overestimation (ED: 15.2g; ES: 8.7g) and narrow 95% limits of agreement (ED: ±30g; ES: ±33g). The automated interpretation resulted in high sensitivity, specificity, and accuracy (78%, 85%, 82%, respectively) of WM abnormalities. Combined automated endo and epicardial border detection from MRI images provides reliable measurements of LV dimensions and regional WM classification.

Diabetes mellitus (DM) and chronic kidney disease (CKD) often coexist, and both are recognized risk factors for future cardiovascular events. Painless myocardial ischemia occurs more commonly in CKD patients than in individuals with normal renal function and is associated with a higher mortality

ArgBP2, encoding a negative regulator of ABL, is fused to MLL in a case of infant M5 acute myeloid leukemia involving 4q35 and 11q23

This study explored the effects of cardiac resynchronization therapy (CRT) on left ventricular (LV) twist, particularly in relation to LV lead position.LV twist is emerging as a comprehensive index of LV function.Eighty heart failure patients were included. Two-dimensional echocardiography was performed at baseline, immediately after CRT, and at 6-month follow-up. Speckle-tracking analysis was applied to assess LV twist. The LV lead was placed preferably in a (postero)lateral vein, and at fluoroscopy, the position was classified as basal, midventricular, or apical. Response to CRT was defined as reduction of LV end-systolic volumeor=15% at 6-month follow-up. A control group comprised 30 normal subjects.Peak LV twist in heart failure patients was 4.8+/-2.6 degrees compared with 15.0+/-3.6 degrees in the control subjects (p0.001). At 6-month follow-up, peak LV twist significantly improved only in responders (56%), from 4.3+/-2.4 degrees to 8.5+/-3.2 degrees (p0.001). The strongest predictor of response to CRT was the improvement of peak LV twist immediately after CRT (odds ratio: 1.899, 95% confidence interval: 1.334 to 2.703, p0.001). Furthermore, LV twist significantly improved in patients with an apical (from 4.3+/-3.1 degrees to 8.6+/-3.0 degrees, p=0.001) and midventricular (from 4.8+/-2.2 degrees to 6.4+/-3.9 degrees, p=0.038) but not with a basal (5.0+/-3.3 degrees vs. 4.1+/-3.2 degrees, p=0.28) LV lead position. Similarly, LV ejection fraction significantly increased in patients with an apical (from 26+/-7% to 37+/-7%, p0.001) and midventricular (from 26+/-6% to 33+/-8%, p0.001) but not with a basal (26+/-5% vs. 28+/-8%, p=0.30) LV lead position.An immediate improvement of LV twist after CRT predicts LV reverse remodeling at 6-month follow-up.

Arrhythmogenic right ventricular dysplasia/cardiomyopathy is a rarely described cause of sudden death among infants. We report the case of a 4-month-old male infant who died suddenly in his sleep. Postmortem examination revealed the presence of arrhythmogenic right ventricular dysplasia/cardiomyopathy.

Aim To study frequency and incremental prognostic value of restrictive filling pattern (RFP) in hypertrophic cardiomyopathy (HCM). Methods and results Eighty-seven consecutive HCM patients (64% men, mean age 45 ± 19 years) underwent physical and Doppler echocardiographic evaluation at our centre from March 1993 to February 2001. Mean length of follow-up was 96 ± 54 months. RFP was found in 14 patients (16%) at index evaluation. Patients with RFP had higher NYHA class, more frequent signs of heart failure and lower left ventricular ejection fraction ( P = 0.018, P = 0.002 and P = 0.001, respectively). During follow-up, cardiac death plus heart transplantation was significantly higher in HCM patients with RFP than in those without RFP ( P = 0.0001). NYHA class (HR = 5.95, 95% CI: 1.34–26.38, P = 0.019), indexed left atrial diameter (HR = 1.68, 95% CI: 1.01–2.82, P = 0.047) and RFP (HR = 2.94, 95% CI: 1.25–6.88, P = 0.01) were selected as predictors of cardiac death or heart transplantation in a multivariate proportional hazard model. The AUC of ROC curve from multivariate regression models for predicting adverse outcome significantly improved from 0.76 considering only NYHA class to 0.84 after inclusion of RFP and indexed left atrial diameter ( P = 0.01). Conclusions RFP is rare, but not exceptional, in HCM. Echo-Doppler evaluation of filling pattern confers additional prognostic power to clinical stratification.