The Hepatic Microenvironment Uniquely Protects Leukemia Cells through Induction of Growth and Survival Pathways Mediated by LIPG.

Due to the disseminated nature of leukemia, malignant cells are exposed to many different tissue microenvironments, including a variety of extramedullary sites. In the present study, we demonstrate that leukemic cells residing in the liver display unique biological properties and also contribute to systemic changes that influence physiologic responses to chemotherapy. Specifically, the liver microenvironment induces metabolic adaptations via upregulating expression of endothelial lipase in leukemia cells, which not only stimulates tumor cell proliferation through polyunsaturated fatty acid-mediated pathways, but also promotes survival by stabilizing antiapoptotic proteins. Additionally, hepatic infiltration and tissue damage caused by malignant cells induces release of liver-derived enzymes capable of degrading chemotherapy drugs, an event that further protects leukemia cells from conventional therapies. Together, these studies demonstrate a unique role for liver in modulating the pathogenesis of leukemic disease and suggest that the hepatic microenvironment may protect leukemia cells from chemotherapeutic challenge. SIGNIFICANCE: The studies presented herein demonstrate that the liver provides a microenvironment in which leukemia cells acquire unique metabolic properties. The adaptations that occur in the liver confer increased resistance to chemotherapy. Therefore, we propose that therapies designed to overcome liver-specific metabolic changes will yield improved outcomes for patients with leukemia.This article is highlighted in the In This Issue feature, p. 211.

An Atmospheric Pressure Chemical Ionization MS/MS Assay Using Online Extraction for the Analysis of 11 Cannabinoids and Metabolites in Human Plasma and Urine.

BACKGROUND: Although, especially in the United States, there has been a recent surge of legalized cannabis for either recreational or medicinal purposes, surprisingly little is known about clinical dose-response relationships, pharmacodynamic and toxicodynamic effects of cannabinoids such as Δ9-tetrahydrocannabinol (THC). Even less is known about other active cannabinoids. METHODS: To address this knowledge gap, an online extraction, high-performance liquid chromatography coupled with tandem mass spectrometry method for simultaneous quantification of 11 cannabinoids and metabolites including THC, 11-hydroxy-Δ9-tetrahydrocannabinol, 11-nor-Δ9-tetrahydrocannabinol-9-carboxylic acid, 11-nor-Δ9-tetrahydrocannabinol-9-carboxylic acid glucuronide (THC-C-gluc), cannabinol, cannabidiol, cannabigerol, cannabidivarin, Δ9-tetrahydrocannabivarin (THCV), and 11-nor-9-carboxy-Δ9-tetrahydrocannabivarin (THCV-COOH) was developed and validated in human urine and plasma. RESULTS: In contrast to atmospheric pressure chemical ionization, electrospray ionization was associated with extensive ion suppression in plasma and urine samples. Thus, the atmospheric pressure chemical ionization assay was validated showing a lower limit of quantification ranging from 0.39 to 3.91 ng/mL depending on study compound and matrix. The upper limit of quantification was 400 ng/mL except for THC-C-gluc with an upper limit of quantification of 2000 ng/mL. The linearity was r > 0.99 for all analyzed calibration curves. Acceptance criteria for intrabatch and interbatch accuracy (85%-115%) and imprecision (<15%) were met for all compounds. In plasma, the only exceptions were THCV (75.3%-121.2% interbatch accuracy) and cannabidivarin (interbatch imprecision, 15.7%-17.2%). In urine, THCV did not meet predefined acceptance criteria for intrabatch accuracy. CONCLUSIONS: This assay allows for monitoring not only THC and its major metabolites but also major cannabinoids that are of interest for marijuana research and clinical practice.