MiR-125 in normal and malignant hematopoiesis.

MiR-125 is a highly conserved microRNA throughout many different species from nematode to humans. In humans, there are three homologs (hsa-miR-125b-1, hsa-miR-125b-2 and hsa-miR-125a). Here we review a recent research on the role of miR-125 in normal and malignant hematopoietic cells. Its high expression in hematopoietic stem cells (HSCs) enhances self-renewal and survival. Its expression in specific subtypes of myeloid and lymphoid leukemias provides resistance to apoptosis and blocks further differentiation. A direct oncogenic role in the hematopoietic system has recently been demonstrated by several mouse models. Targets of miR-125b include key proteins regulating apoptosis, innate immunity, inflammation and hematopoietic differentiation.

Hsa-mir-125b-2 is highly expressed in childhood ETV6/RUNX1 (TEL/AML1) leukemias and confers survival advantage to growth inhibitory signals independent of p53.

MicroRNAs (miRNAs) regulate the expression of multiple proteins in a dose-dependent manner. We hypothesized that increased expression of miRNAs encoded on chromosome 21 (chr 21) contribute to the leukemogenic function of trisomy 21. The levels of chr 21 miRNAs were quantified by qRT-PCR in four types of childhood acute lymphoblastic leukemia (ALL) characterized by either numerical (trisomy or tetrasomy) or structural abnormalities of chr 21. Suprisingly, high expression of the hsa-mir-125b-2 cluster, consisting of three miRNAs, was identified in leukemias with the structural ETV6/RUNX1 abnormality and not in ALLs with trisomy 21. Manipulation of ETV6/RUNX1 expression and chromatin immunoprecipitation studies showed that the high expression of the miRNA cluster is an event independent of the ETV6/RUNX1 fusion protein. Overexpression of hsa-mir-125b-2 conferred a survival advantage to Ba/F3 cells after IL-3 withdrawal or a broad spectrum of apoptotic stimuli through inhibition of caspase 3 activation. Conversely, knockdown of the endogenous miR-125b in the ETV6/RUNX1 leukemia cell line REH increased apoptosis after Doxorubicin and Staurosporine treatments. P53 protein levels were not altered by miR-125b. Together, these results suggest that the expression of hsa-mir-125b-2 in ETV6/RUNX1 ALL provides survival advantage to growth inhibitory signals in a p53-independent manner.

A new locus for autosomal dominant posterior polar cataract in Moroccan Jews maps to chromosome 14q22-23.

BACKGROUND: Posterior polar cataract is a clinically distinctive opacity located at the back of the lens. It is commonly acquired in age related cataract, and may infrequently occur in pedigrees with congenital cataract. To date, five loci for autosomal dominant congenital posterior polar cataract have been identified. These include two genes, CRYAB and PITX3, on chromosomes 11q and 10q respectively, and three loci with as yet unknown genes on chromosomes 1p, 16q and 20p. PURPOSE: To find the chromosomal location of a gene causing autosomal dominant congenital posterior polar cataract in three Moroccan Jewish families. METHODS: A whole genome scan was performed using microsatellite markers spaced at approximately 10 cM intervals. For fine mapping, five additional microsatellite markers were genotyped. Two-point lod scores were calculated using MLINK software, from the LINKAGE program package. After linkage was established, several positional candidate genes were assessed by PCR based DNA sequencing. RESULTS: The new cataract locus was mapped to an 11.3 cM interval between D14S980 and D14S1069 on chromosome 14q22-23. A maximum two point lod score of 5.19 at theta = 0 was obtained with the markersD14S274. The positional and functional candidate genes SIX1, SIX4, SIX6, OTX2, and ARHJ were excluded as the cause of cataract in these families. CONCLUSION: An as yet unidentified gene associated with posterior polar cataract maps to the long arm of chromosome 14q22-23.

In vivo muscle stiffening under bone compression promotes deep pressure sores.

Pressure sores (PS) in deep muscles are potentially fatal and are considered one of the most costly complications in spinal cord injury patients. We hypothesize that continuous compression of the longissimus and gluteus muscles by the sacral and ischial bones during wheelchair sitting increases muscle stiffness around the bone-muscle interface over time, thereby causing muscles to bear intensified stresses in relentlessly widening regions, in a positive-feedback injury spiral. In this study, we measured long-term shear moduli of muscle tissue in vivo in rats after applying compression (35 KPa or 70 KPa for 1/4-2 h, N = 32), and evaluated tissue viability in matched groups (using phosphotungstic acid hematoxylin histology, N = 10). We found significant (1.8-fold to 3.3-fold, p < 0.05) stiffening of muscle tissue in vivo in muscles subjected to 35 KPa for 30 min or over, and in muscles subjected to 70 KPa for 15 min or over. By incorporating this effect into a finite element (FE) model of the buttocks of a wheelchair user we identified a mechanical stress wave which spreads from the bone-muscle interface outward through longissimus muscle tissue. After 4 h of FE simulated motionlessness, 50%-60% of the cross section of the longissimus was exposed to compressive stresses of 35 KPa or over (shown to induce cell death in rat muscle within 15 min). During these 4 h, the mean compressive stress across the transverse cross section of the longissimus increased by 30%-40%. The identification of the stiffening-stress-cell-death injury spiral developing during the initial 30 min of motionless sitting provides new mechanistic insight into deep PS formation and calls for reevaluation of the 1 h repositioning cycle recommended by the U.S. Department of Health.