Characterization of combinatorial histone modifications on lineage-affiliated genes during hematopoietic stem cell myeloid commitment.

Hematopoietic stem cells (HSCs) are multipotent stem cells capable of self-renewal and multilineage differentiation. Mechanisms regulating the maintenance of HSCs' multipotency and differentiation are still unclear. In this study, we observed the role of combinatorial histone modification pattern in the maintenance of HSCs' pluripotency and differentiation. HSCs (CD34(+)CD38(low)) were collected from human umbilical cord blood and induced to differentiate to committed cells in vitro. The histone modifications on lineage-specific transcription factors/genes in multipotent HSCs and differentiated progenies, including megakaryocytes, granulocytes, and erythrocytes, were analyzed by chromatin immunoprecipitation-quantitative polymerase chain reaction. Our results showed that a certain level of acH4 and acH3 together with high level of H3K4me2, low level of H3K4me3, and a certain level of H3K9me3 and H3K27me3 were present in lineage-specific genes in CD34(+)CD38(low) HSCs. As CD34(+)CD38(low) cells differentiated into granulocytes, erythroid cells, and megakaryocytes, the modification levels of acH3, acH4, and H3K4me2 on lineage-specific genes remained the same or elevated, while H3K4me3 level was increased greatly. At the same time, H3K9me3 and H3K27me3 modification levels became lower. In non-lineage-specific genes, the acH3 and acH4 levels were decreased, and H3K4me3 level remained at low level, while H3K9me3 and H3K27me3 levels were increased drastically. Our data suggest that combinatorial histone modification patterns have implicated function in maintaining the multipotency of HSCs and keeping the accuracy of gene expression program during HSC differentiation.

A small molecule significantly inhibits the bcr/abl fusion gene at the mRNA level in human chronic myelogenous leukemia.

Bcr/abl fusion gene is the marker gene in chronic myelogenous leukemia (CML) and becomes the target for CML therapy. Although Imatinib opened a new way to treat CML, the resistance to the drug caused by bcr/abl fusion protein mutation stimulated search for new molecules to inhibit bcr/abl expression. In our research, it was found that a novel 2-aminosteroid (H89465) possessed special mechanism in treating CML. H89465 inhibits the proliferation of both non-resistant and resistant CML cells such as K562, Meg-01 and clinical primary CML cells. It prolongs the survival time of NOD/SCID mice inoculated with K562 leukemia cells. The mechanism underlying the effects is concerned with down-regulation of bcr/abl mRNA expression followed by decreasing the BCR/ABL protein expression and tyrosine kinase activity in CML cells. Our results demonstrate that H89465 possesses the therapeutic potential in treating human CML.

Multiple outbreaks of acute hemorrhagic conjunctivitis due to a variant of coxsackievirus A24: Guangdong, China, 2007.

Acute hemorrhagic conjunctivitis (AHC) is usually caused by enterovirus 70, coxsackievirus A24(CA24v) and adenoviruses. Several outbreaks of AHC caused by a CA24v have occurred since it was imported into China in 1971. Multiple outbreaks of AHC reappeared in 10 cities of Guangdong during June to November in 2007. The epidemic began in the June, and spread extensively, with a peak in the September. A total of 31,659 cases were reported to center for disease control and prevention of Guangdong, it was estimated that the number of actual AHC was >200 thousands. Forty conjunctival swab specimens were collected from the cases diagnosed clinically with AHC. (RT)-PCR testing on these conjunctival specimens revealed the presence of an enterovirus, and this was confirmed by 16 isolates. We demonstrated the most likely etiological agent for the multiple outbreaks was a variant of coxsackievirus A24 by molecular typing using a partial VP1 sequence. Sequence comparison and phylogenetic analyses of the VP1 and 3Cpro gene regions were performed by Neighbor-joining method, the strains from different outbreaks and different geographical areas within Guangdong had no sequence divergence in 2007. The representative isolates from mainland of China including Hangzhou, Ningbo, Beijing, Yunnan, Liaoning, and Henan were analyzed in this study. Phylogenetic analysis revealed theses isolates were located in different clusters, a close phylogenetic and chronological relationship with Singaporean, South Korean and Thailand isolates had been observed. This confirms CA24v circulated in China's mainland has not evolved independently, but co-evolved with the isolates of Southeast Asia.