PI3Kδ inhibition elicits anti-leukemic effects through Bim-dependent apoptosis

Abstract

PI3Kδ plays pivotal roles in the maintenance, proliferation and survival of malignant B-lymphocytes. Although not curative, PI3Kδ inhibitors (PI3Kδi) demonstrate impressive clinical efficacy and, alongside other signaling inhibitors, are revolutionizing the treatment of hematological malignancies. However, only limited in vivo data are available regarding their mechanism of action. With the rising number of novel treatments, the challenge is to identify combinations that deliver curative regimes. A deeper understanding of the molecular mechanism is required to guide these selections. Currently, immunomodulation, inhibition of B-cell receptor signaling, chemokine/cytokine signaling and apoptosis represent potential therapeutic mechanisms for PI3Kδi. Here we characterize the molecular mechanisms responsible for PI3Kδi-induced apoptosis in an in vivo model of chronic lymphocytic leukemia (CLL). In vitro, PI3Kδi-induced substantive apoptosis and disrupted microenvironment-derived signaling in murine (Eμ-Tcl1) and human (CLL) leukemia cells. Furthermore, PI3Kδi imparted significant therapeutic responses in Eμ-Tcl1-bearing animals and enhanced anti-CD20 monoclonal antibody therapy. Responses correlated with upregulation of the pro-apoptotic BH3-only protein Bim. Accordingly, Bim−/− Eμ-Tcl1 Tg leukemias demonstrated resistance to PI3Kδi-induced apoptosis were refractory to PI3Kδi in vivo and failed to display combination efficacy with anti-CD20 monoclonal antibody therapy. Therefore, Bim-dependent apoptosis represents a key in vivo therapeutic mechanism for PI3Kδi, both alone and in combination therapy regimes.

Antibody Tumor Targeting Is Enhanced by CD27 Agonists through Myeloid Recruitment

“…1 x 10 7 Eμ-TCL1 cells were intraperitoneally injected into groups of 6- to 8-week old female C57BL/6 mice and leukemic burden monitored by tail bleeds and CD5/B220 expression through flow cytometry as before ( Carter et al., 2016 ). Animals were treated with anti-CD20 (250 μg) and anti-CD27 (100 μg) 1 day later when more than 10% B220 + CD5 int lymphocytes were present in the blood.…”

The PI3Kδ-Selective Inhibitor Idelalisib Minimally Interferes with Immune Effector Function Mediated by Rituximab or Obinutuzumab and Significantly Augments B Cell Depletion In Vivo

“…Following disease presentation, mice were treated with 250 μg of anti-mouse CD20 (clone 18B12 mouse IgG2a), 250 μg of rituximab (human IgG1 [hIgG1]), or 250 μg of obinutuzumab (hIgG1) by i.p. injection, together with 10 mg/kg GS-9820 by mouth twice a day or an appropriate vehicle control, as described previously ( 21 ). Disease progression/therapeutic responses were subsequently monitored by blood sampling and flow cytometry.…”

Fork Head Box Class O1 (FOXO1) Activates Bim Expression to Mediate Cardiac Apoptosis in Chronic Intermittent Hypoxia-Induced Cardiac Hypertrophy

“…Cardiomyocyte apoptosis is a major decisive factor of cardiac hypertrophy [ 6 , 7 ]. Bim, a BH3-only Bcl-2 protein, initiates apoptosis by promoting the release of mitochondrial cytochrome C, which in turn activates caspase3 and eventually leads to apoptosis [ 8 ]. It has been reported that Bim exists in 3 major isoforms (BimS, BimL, and BimEL) that are generated by alternative splicing of a number of transcripts [ 9 ].…”