SUMMARY Genetically modified T cells expressing chimeric antigen receptors (CARs) demonstrate robust responses against lineage restricted, non-essential targets in hematologic cancers. However, in solid tumors, the full potential of CAR T cell therapy is limited by the availability of cell surface antigens with sufficient cancer-specific expression. The majority of CAR targets have been normal self-antigens on dispensable hematopoietic tissues or overexpressed shared antigens. Here, we established that abnormal self-antigens can serve as targets for tumor rejection. We developed a CAR that recognized cancer-associated Tn glycoform of MUC1, a neoantigen expressed in a variety of cancers. Anti-Tn-MUC1 CAR T cells demonstrated target-specific cytotoxicity and successfully controlled tumor growth in xenograft models of T cell leukemia and pancreatic cancer. These findings demonstrate the therapeutic efficacy of CAR T cells directed against Tn-MUC1 and present aberrantly glycosylated antigens as a novel class of targets for tumor therapy with engineered T cells.

Park et al describe a novel KLF4-mediated pathway that promotes chromic myeloid leukemia (CML) stem cell (LSC) survival. Deletion of KLF4 in a mouse model of CML decreases LSC survival through repression of Dyrk2, resulting in c-Myc depletion and increased p53 activity.

Acute lymphoblastic leukemia (ALL) is the most common hematological malignancy in pediatric patients. Despite advances in the treatment of this disease, many children with T-cell ALL (T-ALL) die from disease relapse due to low responses to standard chemotherapy and the lack of a targeted therapy that selectively eradicates the chemoresistant leukemia-initiating cells (LICs) responsible for disease recurrence. We recently reported that the reprogramming factor KLF4 has tumor-suppressive function in children with T-ALL. KLF4 silencing by promoter DNA methylation in patients with T-ALL leads to aberrant activation of MAP2K7 kinase and the downstream JNK pathway that controls the expansion of leukemia cells via c-JUN and ATF2. This pathway can be inhibited with small molecules and therefore has the potential to eliminate LICs and eradicate disease in combination with standard therapy for patients with refractory and relapsed disease. The present review summarizes the role of the KLF4-MAP2K7 pathway in T-ALL pathogenesis and the function of JNK and MAP2K7 in carcinogenesis and therapy.

Since antibiotic development lags, we search for potential drug targets through directed evolution experiments. A challenge is that many resistance genes hide in a noisy mutational background as mutator clones emerge in the adaptive population. Here, to overcome this noise, we quantify the impact of mutations through evolutionary action (EA). After sequencing ciprofloxacin or colistin resistance strains grown under different mutational regimes, we find that an elevated sum of the evolutionary action of mutations in a gene identifies known resistance drivers. This EA integration approach also suggests new antibiotic resistance genes which are then shown to provide a fitness advantage in competition experiments. Moreover, EA integration analysis of clinical and environmental isolates of antibiotic resistant of E. coli identifies gene drivers of resistance where a standard approach fails. Together these results inform the genetic basis of de novo colistin resistance and support the robust discovery of phenotype-driving genes via the evolutionary action of genetic perturbations in fitness landscapes.