Loss of the xeroderma pigmentosum group B protein binding site impairs p210 BCR/ABL1 leukemogenic activity

Previous studies have demonstrated that p210 BCR/ABL1 interacts directly with the xeroderma pigmentosum group B (XPB) protein, and that XPB is phosphorylated on tyrosine in cells that express p210 BCR/ABL1. In the current study, we have constructed a p210 BCR/ABL1 mutant that can no longer bind to XPB. The mutant has normal kinase activity and interacts with GRB2, but can no longer phosphorylate XPB. Loss of XPB binding is associated with reduced expression of c-MYC and reduced transforming potential in ex-vivo clonogenicity assays, but does not affect nucleotide excision repair in lymphoid or myeloid cells. When examined in a bone marrow transplantation (BMT) model for chronic myelogenous leukemia, mice that express the mutant exhibit attenuated myeloproliferation and lymphoproliferation when compared with mice that express unmodified p210 BCR/ABL1. Thus, the mutant-transplanted mice show predominantly neutrophilic expansion and altered progenitor expansion, and have significantly extended lifespans. This was confirmed in a BMT model for B-cell acute lymphoblastic leukemia, wherein the majority of the mutant-transplanted mice remain disease free. These results suggest that the interaction between p210 BCR/ABL1 and XPB can contribute to disease progression by influencing the lineage commitment of lymphoid and myeloid progenitors

Curing of Plasmid pXO1 from Bacillus anthracis Using Plasmid Incompatibility

The large plasmid pXO1 encoding the anthrax toxin is important for the virulence of Bacillus anthracis. It is essential to cure pXO1 from B. anthracis to evaluate its role in the pathogenesis of anthrax infection. Because conventional methods for curing plasmids (e.g., curing agents or growth at elevated temperatures) can induce mutations in the host chromosomal DNA, we developed a specific and reliable method to eliminate pXO1 from B. anthracis using plasmid incompatibility. Three putative replication origins of pXO1 were inserted into a temperature-sensitive plasmid to generate three incompatible plasmids. One of the three plasmids successfully eliminated the large plasmid pXO1 from B. anthracis vaccine strain A16R and wild type strain A16. These findings provided additional information about the replication/partitioning of pXO1 and demonstrated that introducing a small incompatible plasmid can generate plasmid-cured strains of B. anthracis without inducing spontaneous mutations in the host chromosome

Individualized Venous Thromboembolism Risk Stratification and Chemoprophylaxis in Surgical Patients

Venous thromboembolism (VTE) can occur following a surgical procedure, and is usually prevented using anticoagulant chemoprophylaxis. The risk/benefit ratio of chemoprophylaxis, however, varies among individual patients; surgical patients at low risk for VTE may not benefit from chemoprophylaxis, but still be subjected to the bleeding risk. The research team of Christopher Pannucci, MD, and Benjamin Brooke, MD, set out to determine whether chemoprophylaxis for VTE among surgical patients could be better achieved through individualized risk stratification using established Caprini scores. They performed a meta-analysis of nearly 15,000 surgery patients, stratified by Caprini scores for VTE risk levels. When chemoprophylaxis was provided peri-operatively, high-risk patients (Caprini scores >7) exhibited significant VTE risk-reduction without significant increase in bleeding. In comparison, 75% of low-risk patients (Caprini scores <6) had an unfavorable risk/benefit ratio and, therefore, chemoprophylaxis was unwarranted. This study highlights the benefits of a precision-medicine (i.e., risk-stratification) approach to VTE prevention and has important practice implications