Targeting ER stress response in B-cell chronic lymphocytic leukemia

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Project Summary/Abstract Chronic lymphocytic leukemia (CLL) is an incurable B cell malignancy that represents 30% of all adult leukemia. Although the initiating events are unclear, exposure to factors such as bacterial polysaccharides, lipoproteins, and DNA has been proposed to drive proliferation in CLL, via binding to the B cell receptor (BCR). These factors also serve as ligands for Toll-like receptors (TLRs), a class of receptors critical for innate immunity and that play multiple roles in B cell differentiation and activation. However, exactly how TLR ligands are involved in CLL is unclear, as some studies observe apoptosis after treatment of CLL cells with TLR ligands and other studies observe proliferation. Understanding which ligands have which effects is particularly crucial at present, as TLR ligands are proposed as immunomodulatory agents to coach our immune system to combat CLL. As a clinical case in point, ibrutinib is used to inhibit the BCR signaling that drives proliferation of CLL; but approximately 60% of CLL patients treated with ibrutinib at the Moffitt Cancer Center dropped out of the therapy due to toxicity. In addition, CLL undergoes Richter's transformation into fast-growing diffuse large B cell lymphoma in increasing numbers of patients receiving ibrutinib therapy. Hence, halting B cell proliferation in CLL remains a challenge. Our group used our in-depth understanding of the endoplasmic reticulum (ER) signaling to consider this problem from a different angle, finding that for CLL cells to survive they require activation of the ER stress response. We also found that the IRE-1/XBP-1 pathway of the ER stress response is activated by TLR ligands, to promote proliferation of CLL cells in vitro. These results led us to hypothesize that in CLL cells, specific TLR ligands activate the IRE-1/XBP-1 pathway through TLR and BCR signaling, to promote malignant progression of CLL. We have generated a novel mouse model in which the XBP-1 gene is knocked out specifically in B cells in Eµ-TCL1 (CLL) mice, and showed that BCR signaling is downregulated in XBP-1-deficient Eµ-TCL1 B cells. In addition, we have developed a specific and potent inhibitor of the IRE- 1/XBP-1 pathway, B-I09, which induces apoptosis of CLL in vivo and does not exhibit overt toxicity in mice. Treatment with B-I09 also reduced BCR signaling in Eµ-TCL1 B cells. Using these novel tools, we will determine exactly which TLR ligands promote malignant progression of CLL in vivo via activation of the IRE- 1/XBP-1 pathway and BCR signaling, and whether targeting the IRE-1/XBP-1 pathway can thwart the two- pronged effect of TLR ligands. Based on our new data, we also propose to test whether CLL cells lacking XBP- 1s may activate regulated IRE-1-dependent decay (RIDD) to counter apoptosis. These goals are summarized in the following specific aims. Aim 1: Establish that TLR ligand-induced activation of the ER stress response supports malignant progression of CLL in vivo, and proliferation and survival of human CLL cells. Aim 2: Investigate whether targeting XBP-1 decelerates TLR ligand-induced progression of CLL by suppressing BCR signaling. Aim 3: Investigate how RIDD contributes to the progression of CLL in XBP-1KO/Eµ-TCL1 mice.