Targeting ER stress response in B-cell chronic lymphocytic leukemia

Methodist Hospital Research Institute, Houston TX

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Abstract

Project Summary/Abstract Chronic lymphocytic leukemia (CLL) is an incurable B cell malignancy that represents 30% of all adult leukemia. To help combat CLL, we aim to investigate the aggressive behavior of CLL and develop novel combinatorial therapeutic strategies. Previously, we have shown that the IRE-1/XBP-1s pathway of the endoplasmic reticulum (ER) stress response is critically important for supporting malignant progression of CLL in mice. Nevertheless, the factor that drives activation of the IRE-1/XBP-1s pathway in CLL remains unknown. Clinically, the mutational status of the immunoglobulin heavy chain locus (IgHV) is an important prognostic indicator for CLL progression and treatment outcome. Human CLL patients with mutated IgHV survive longer and have a better response to chemotherapy than those with unmutated IgHV. We have recently shown that aggressive IgHV-unmutated human CLL samples indeed produce significantly higher mRNA levels of XBP-1s than indolent IgHV-mutated samples. Because this immunoglobulin mutation status is exclusively mediated by activation-induced cytidine deaminase (AID), we decided to generate an AID-deficient CLL mouse model in which IgHV could not be mutated. We found that the resultant mice indeed survived significantly shorter than their AID-proficient counterparts, consistent with the fact that IgHV-unmutated human CLL cells are more aggressive. Like aggressive IgHV-unmutated human CLL cells, AID-deficient mouse CLL cells also expressed higher levels of XBP-1s and were more responsive to activation of the B cell receptor (BCR) than their AID- proficient counterparts. Because AID-deficient CLL cells also produced significantly higher levels of secretory IgM (sIgM), the largest antibody, than AID-proficient CLL cells, we hypothesized that the increased production of sIgM in CLL cells is the major factor that drives activation of the IRE-1/XBP-1s pathway to increase the folding capability of the ER and protect CLL cells from dying of proteotoxicity as a result of accumulations of misfolded components of sIgM in the ER. We thus propose to genetically delete the capability of producing sIgM in IgHV-unmutated CLL cells to support our hypothesis. Acknowledging that both XBP-1s and BCR signaling are significantly upregulated in IgHV-unmutated CLL cells, we propose to investigate whether the combination of B-I09 (an XBP-1s inhibitor) and a Bruton's tyrosine kinase inhibitor (BTKi) will be more effective in killing such CLL cells in vivo. Finally, because deleting the capability of B cells in making sIgM will lead to increased production of secretory IgG (sIgG), we propose to evaluate the roles of sIgG in controlling CLL. Our goals are summarized in the following specific aims. Aim 1: Establish the roles of sIgM in activating the IRE- 1/XBP-1s pathway to support malignant progression of IgHV-unmutated CLL. Aim 2: Examine whether the combination of B-I09 and BTKi is more effective in inhibiting the growth of IgHV-unmutated CLL cells that express higher levels of sIgM and XBP-1s. Aim 3: Examine whether sIgG can enhance the activity of B-I09 or BTKi in suppressing the growth of IgHV-unmutated CLL in mice.