Requirement for antiapoptotic MCL-1 during early erythropoiesis.

Although BCL-xL is critical to the survival of mature erythrocytes, it is still unclear whether other antiapoptotic molecules mediate survival during earlier stages of erythropoiesis. Here, we demonstrate that erythroid-specific Mcl1 deletion results in embryonic lethality beyond embryonic day 13.5 as a result of severe anemia caused by a lack of mature red blood cells (RBCs). Mcl1-deleted embryos exhibit stunted growth, ischemic necrosis, and decreased RBCs in the blood. Furthermore, we demonstrate that MCL-1 is only required during early definitive erythropoiesis; during later stages, developing erythrocytes become MCL-1 independent and upregulate the expression of BCL-xL. Functionally, MCL-1 relies upon its ability to prevent apoptosis to promote erythroid development because codeletion of the proapoptotic effectors Bax and Bak can overcome the requirement for MCL-1 expression. Furthermore, ectopic expression of human BCL2 in erythroid progenitors can compensate for Mcl1 deletion, indicating redundancy between these 2 antiapoptotic family members. These data clearly demonstrate a requirement for MCL-1 in promoting survival of early erythroid progenitors.

DNA damage response genes mark the early transition from colitis to neoplasia in colitis-associated colon cancer.

Chronic intestinal inflammation predisposes patients with Inflammatory Bowel Disease (IBD) to Colitis-Associated Cancer (CAC). In the setting of chronic inflammation, microsatellite instability (MSI) results from early loss of DNA damage response (DDR) genes, ultimately leading to tumor formation. Despite continued efforts to improve early detection of high risk, pre-dysplastic regions in IBD patients, current macroscopic and genetic surveillance modalities remain limited. Therefore, understanding the regulation of key DDR genes in the progression from colitis to cancer may improve molecular surveillance of CAC. To evaluate DDR gene regulation in the transition from colitis to tumorigenesis, we utilized the well-established Azoxymethane/Dextran Sodium Sulfate (AOM/DSS) pre-clinical murine model of CAC in C57BL/6 mice. In order to assess colonic tumor burden in the setting of mutagen and intestinal irritation, tumors were visualized and graded in real time through high-resolution murine colonoscopy. Upon sacrifice, colons were opened and assessed for macroscopic tumor via high magnification surgical lenses (HMSL). Tissues were then sectioned and separated into groups based on the presence or absence of macroscopically visible tumor. Critical DDR genes were evaluated by semi-quantitative RT-PCR. Interestingly, colon tissue with macroscopically visible tumor (MVT) and colon tissue prior to observable tumor (the non-macroscopically visible tumor-developing group, NMVT) were identical in reduced mRNA expression of mlh1, anapc1, and ercc4 relative to colitic mice without mutagen, or those receiving mutagen alone. Colitis alone was sufficient to reduce colonic ercc4 expression when compared to NMVT mice. Therefore, reduced ercc4 expression may mark the early transition to CAC in a pre-clinical model, with expression reduced prior to the onset of observable tumor. Moreover, the expression of select DDR genes inversely correlated with chronicity of inflammatory disease. These data suggest ercc4 expression may define early stages in the progression to CAC.

Genome sequences of five b1 subcluster mycobacteriophages.

Mycobacteriophages infect members of the Mycobacterium genus in the phylum Actinobacteria and exhibit remarkable diversity. Genome analysis groups the thousands of known mycobacteriophages into clusters, of which the B1 subcluster is currently the third most populous. We report the complete genome sequences of five additional members of the B1 subcluster.