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Disruption of IRE1? through its kinase domain attenuates multiple myeloma.

ABSTRACT: Multiple myeloma (MM) arises from malignant immunoglobulin (Ig)-secreting plasma cells and remains an incurable, often lethal disease despite therapeutic advances. The unfolded-protein response sensor IRE1? supports protein secretion by deploying a kinase-endoribonuclease module to activate the transcription factor XBP1s. MM cells may co-opt the IRE1?-XBP1s pathway; however, the validity of IRE1? as a potential MM therapeutic target is controversial. Genetic disruption of IRE1? or XBP1s, or pharmacologic IRE1? kinase inhibition, attenuated subcutaneous or orthometastatic growth of MM tumors in mice and augmented efficacy of two established frontline antimyeloma agents, bortezomib and lenalidomide. Mechanistically, IRE1? perturbation inhibited expression of key components of the endoplasmic reticulum-associated degradation machinery, as well as secretion of Ig light chains and of cytokines and chemokines known to promote MM growth. Selective IRE1? kinase inhibition reduced viability of CD138+ plasma cells while sparing CD138- cells derived from bone marrows of newly diagnosed or posttreatment-relapsed MM patients, in both US- and European Union-based cohorts. Effective IRE1? inhibition preserved glucose-induced insulin secretion by pancreatic microislets and viability of primary hepatocytes in vitro, as well as normal tissue homeostasis in mice. These results establish a strong rationale for developing kinase-directed inhibitors of IRE1? for MM therapy.

SUBMITTER: Harnoss JM

PROVIDER: S-EPMC6697881 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Disruption of IRE1α through its kinase domain attenuates multiple myeloma.

Harnoss Jonathan M JM Harnoss Jonathan M JM Le Thomas Adrien A Shemorry Anna A Marsters Scot A SA Lawrence David A DA Lu Min M Chen Yung-Chia Ariel YA Qing Jing J Totpal Klara K Kan David D Segal Ehud E Merchant Mark M Reichelt Mike M Ackerly Wallweber Heidi H Wang Weiru W Clark Kevin K Kaufman Susan S Beresini Maureen H MH Laing Steven T ST Sandoval Wendy W Lorenzo Maria M Wu Jiansheng J Ly Justin J De Bruyn Tom T Heidersbach Amy A Haley Benjamin B Gogineni Alvin A Weimer Robby M RM Lee Dong D Braun Marie-Gabrielle MG Rudolph Joachim J VanWyngarden Michael J MJ Sherbenou Daniel W DW Gomez-Bougie Patricia P Amiot Martine M Acosta-Alvear Diego D Walter Peter P Ashkenazi Avi A

Proceedings of the National Academy of Sciences of the United States of America 20190801 33

Multiple myeloma (MM) arises from malignant immunoglobulin (Ig)-secreting plasma cells and remains an incurable, often lethal disease despite therapeutic advances. The unfolded-protein response sensor IRE1α supports protein secretion by deploying a kinase-endoribonuclease module to activate the transcription factor XBP1s. MM cells may co-opt the IRE1α-XBP1s pathway; however, the validity of IRE1α as a potential MM therapeutic target is controversial. Genetic disruption of IRE1α or XBP1s, or phar ...[more]

PMID: 31371506

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Project description:Histone modifications associated with gene silencing typically mark large contiguous regions of the genome forming repressive chromatin domain structures. Since the repressive domains exist in close proximity to active regions, maintenance of domain structure is critically important. This study shows that nickel, a nonmutagenic carcinogen, can disrupt histone H3 lysine 9 dimethylation (H3K9me2) domain structures genome-wide, resulting in spreading of H3K9me2 marks into the active regions, which is associated with gene silencing. Our results suggest inhibition of DNA binding of the insulator protein CCCTC-binding factor (CTCF) at the H3K9me2 domain boundaries as a potential reason for H3K9me2 domain disruption. These findings have major implications in understanding chromatin dynamics and the consequences of chromatin domain disruption during pathogenesis. Investigations into the genomic landscape of histone modifications in heterochromatic regions have revealed histone H3 lysine 9 dimethylation (H3K9me2) to be important for differentiation and maintaining cell identity. H3K9me2 is associated with gene silencing and is organized into large repressive domains that exist in close proximity to active genes, indicating the importance of maintenance of proper domain structure. Here we show that nickel, a nonmutagenic environmental carcinogen, disrupted H3K9me2 domains, resulting in the spreading of H3K9me2 into active regions, which was associated with gene silencing. We found weak CCCTC-binding factor (CTCF)-binding sites and reduced CTCF binding at the Ni-disrupted H3K9me2 domain boundaries, suggesting a loss of CTCF-mediated insulation function as a potential reason for domain disruption and spreading. We furthermore show that euchromatin islands, local regions of active chromatin within large H3K9me2 domains, can protect genes from H3K9me2-spreadingM-bM-^@M-^Sassociated gene silencing. These results have major implications in understanding H3K9me2 dynamics and the consequences of chromatin domain disruption during pathogenesis.

Dataset Information

Disruption of IRE1? through its kinase domain attenuates multiple myeloma.

Publications

Disruption of IRE1α through its kinase domain attenuates multiple myeloma.

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