Negative feedback regulation of MAPK signaling is an important driver of chronic lymphocytic leukemia progression.

Despite available targeted treatments for the disease, drug-resistant chronic lymphocytic leukemia (CLL) poses a clinical challenge. The objective of this study is to examine whether the dual-specific phosphatases DUSP1 and DUSP6 are required to negatively regulate mitogen-activated protein kinases (MAPKs) and thus counterbalance excessive MAPK activity. We show that high expression of DUSP6 in CLL correlates with poor clinical prognosis. Importantly, genetic deletion of the inhibitory phosphatase DUSP1 or DUSP6 and blocking DUSP1/6 function using a small-molecule inhibitor reduces CLL cell survival in vitro and in vivo. Using global phospho-proteome approaches, we observe acute activation of MAPK signaling by DUSP1/6 inhibition. This promotes accumulation of mitochondrial reactive oxygen species and, thereby, DNA damage and apoptotic cell death in CLL cells. Finally, we observe that DUSP1/6 inhibition is particularly effective against treatment-resistant CLL and therefore suggest transient DUSP1/6 inhibition as a promising treatment concept to eliminate drug-resistant CLL cells.

Bone marrow stroma cells promote induction of a chemoresistant and prognostic unfavorable S100A8/A9high AML cell subset.

The bone marrow (BM) stroma represents a protective niche for acute myeloid leukemia (AML) cells. However, the complex underlying mechanisms remain to be fully elucidated. We found 2 small, intracellular, calcium-sensing molecules, S100A8 and S100A9, among the top genes being upregulated in primary AML blasts upon stromal contact. As members of the S100 protein family, they can modulate such cellular processes as proliferation, migration, and differentiation. Dysregulation of S100 proteins is described as a predictor of poor survival in different human cancers, including increased S100A8 expression in de novo AML. Thus, we wanted to decipher the underlying pathways of stroma-mediated S100A8/A9 induction, as well as its functional consequences. Upregulation of S100A8/A9 after stromal cross talk was validated in AML cell lines, was contact independent and reversible and resulted in accumulation of S100A8/A9high cells. Accordingly, frequency of S100A8/A9high AML blasts was higher in the patients' BM than in peripheral blood. The S100A8/A9high AML cell population displayed enhanced utilization of free fatty acids, features of a more mature myeloid phenotype, and increased resilience toward chemotherapeutics and BCL2 inhibition. We identified stromal cell-derived interleukin-6 (IL-6) as the trigger for a Jak/STAT3 signaling-mediated S100A8/A9 induction. Interfering with fatty acid uptake and the IL-6-Jak/STAT3 pathway antagonized formation of S100A8/A9high cells and therapeutic resistance, which could have therapeutic implications as a strategy to interfere with the AML-niche dynamics.

Targeted PI3K/AKT-hyperactivation induces cell death in chronic lymphocytic leukemia.

Current therapeutic approaches for chronic lymphocytic leukemia (CLL) focus on the suppression of oncogenic kinase signaling. Here, we test the hypothesis that targeted hyperactivation of the phosphatidylinositol-3-phosphate/AKT (PI3K/AKT)-signaling pathway may be leveraged to trigger CLL cell death. Though counterintuitive, our data show that genetic hyperactivation of PI3K/AKT-signaling or blocking the activity of the inhibitory phosphatase SH2-containing-inositol-5'-phosphatase-1 (SHIP1) induces acute cell death in CLL cells. Our mechanistic studies reveal that increased AKT activity upon inhibition of SHIP1 leads to increased mitochondrial respiration and causes excessive accumulation of reactive oxygen species (ROS), resulting in cell death in CLL with immunogenic features. Our results demonstrate that CLL cells critically depend on mechanisms to fine-tune PI3K/AKT activity, allowing sustained proliferation and survival but avoid ROS-induced cell death and suggest transient SHIP1-inhibition as an unexpectedly promising concept for CLL therapy.