Decreased mitochondrial apoptotic priming underlies stroma-mediated treatment resistance in chronic lymphocytic leukemia

Stroma induces treatment resistance in chronic lymphocytic leukemia (CLL), possibly because of alterations in the BCL-2 family of proteins, which are key regulators of apoptosis. We previously developed BH3 profiling, a functional assay that assesses mitochondrial depolarization in response to BH3-only peptides, to measure “apoptotic priming,” the proximity of a cell to the apoptotic threshold. In the present study, we use BH3 profiling to show that CLL cells from the PB are highly primed. Increased priming is associated with improved clinical response and, unexpectedly, with unmutated IGHV status. Coculturing CLL cells in vitro with stroma decreases priming. Using matched PB, BM, and lymph node compartment samples, we found in vivo that BM-derived CLL cells are the least primed. CLL cells cocultured with stroma were treated with the PI3K δ-isoform inhibitor CAL-101 (GS1101). CAL-101 caused CLL cell de-adhesion, leading to increased CLL cell priming. Stimulation of CLL cells with anti-IgM or CXCL12 caused decreased priming that could be reversed by CAL-101. Our results show that inhibition of stromal interactions leading to displacement of CLL cells into the blood by CAL-101 in vivo may increase CLL cell priming, suggesting a mechanism by which agents inducing lymphocyte redistribution might facilitate improved clinical response when used in combina-tion with other therapies.

Well-Differentiated Thyroid Carcinomas: Management of the Central Lymph Node Compartment and Emerging Biochemical Markers

Well-differentiated thyroid cancers (WDTCs) are generally indolent cancers that are associated with a low mortality. Although the incidence of these tumors is increasing, there has not been an associated increase in the mortality rates. As we gain a greater understanding and more experience with these good prognosis cancers, the way in which we treat these tumors is evolving. The definition of persistent or recurrent disease has seen a shift from being a clinical and/or radiological diagnosis to now one based on a biochemical blood marker, thyroglobulin. Central lymph node metastases are a very common problem in WDTC, being present in up to 90% of patients. The optimal surgical management of the central lymph node compartment remains a hotly debated topic. This paper identifies these controversies and presents available data surrounding these issues. Biochemical tumor markers are gaining wider use in practice and in time hopefully provide more specific information with which surgical decision-making can be based. A summary of the clinically available markers is presented.