Genome-Wide Identification of Variants Associated with Antifungal Drug Resistance.

Genomic approaches are widely applied to study the genetic basis of antifungal drug resistance in clinical isolates and experimental studies. Whole-genome sequencing of clinical isolates can comprehensively identify mutations associated with drug resistance and their frequency across fungal populations. In addition, genome comparison of serially collected isolates, such as from patient samples or in vitro drug selection experiments, will identify a small number of changes that can be evaluated for association with drug resistance.

The immune microenvironment shapes transcriptional and genetic heterogeneity in chronic lymphocytic leukemia.

In chronic lymphocytic leukemia (CLL), B-cell receptor signaling, tumor-microenvironment interactions, and somatic mutations drive disease progression. To better understand the intersection between the microenvironment and molecular events in CLL pathogenesis, we integrated bulk transcriptome profiling of paired peripheral blood (PB) and lymph node (LN) samples from 34 patients. Oncogenic processes were upregulated in LN compared with PB and in immunoglobulin heavy-chain variable (IGHV) region unmutated compared with mutated cases.

Mitochondrial Reprogramming Underlies Resistance to BCL-2 Inhibition in Lymphoid Malignancies.

Mitochondrial apoptosis can be effectively targeted in lymphoid malignancies with the FDA-approved B cell lymphoma 2 (BCL-2) inhibitor venetoclax, but resistance to this agent is emerging. We show that venetoclax resistance in chronic lymphocytic leukemia is associated with complex clonal shifts. To identify determinants of resistance, we conducted parallel genome-scale screens of the BCL-2-driven OCI-Ly1 lymphoma cell line after venetoclax exposure along with integrated expression profiling and functional characterization of drug-resistant and engineered cell lines.