A mechanistic rationale for targeting the unfolded protein response in pre-B acute lymphoblastic leukemia
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE53685 | GEO | 2014/04/24
SECONDARY ACCESSION(S): PRJNA232633
REPOSITORIES: GEO
Similar Datasets
Project description:The unfolded protein response (UPR) pathway, a stress-induced signaling cascade emanating from the endoplasmic reticulum (ER), regulates the expression and activity of molecules including BiP (HSPA5), IRE1 (ERN1), Blimp-1 (PRDM1), and X-box binding protein 1 (XBP1). These molecules are required for terminal differentiation of B cells into plasma cells and expressed at high levels in plasma cell-derived multiple myeloma. Although these molecules have no known role at early stages of B-cell development, here we show that their expression transiently peaks at the pre-B-cell receptor checkpoint. Inducible, Cre-mediated deletion of Hspa5, Prdm1, and Xbp1 consistently induces cellular stress and cell death in normal pre-B cells and in pre-B-cell acute lymphoblastic leukemia (ALL) driven by BCR-ABL1- and NRAS(G12D) oncogenes. Mechanistically, expression and activity of the UPR downstream effector XBP1 is regulated positively by STAT5 and negatively by the B-cell-specific transcriptional repressors BACH2 and BCL6. In two clinical trials for children and adults with ALL, high XBP1 mRNA levels at the time of diagnosis predicted poor outcome. A small molecule inhibitor of ERN1-mediated XBP1 activation induced selective cell death of patient-derived pre-B ALL cells in vitro and significantly prolonged survival of transplant recipient mice in vivo. Collectively, these studies reveal that pre-B ALL cells are uniquely vulnerable to ER stress and identify the UPR pathway and its downstream effector XBP1 as novel therapeutic targets to overcome drug resistance in pre-B ALL.
| S-EPMC4040579 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2014-04-24 | E-GEOD-53685 | biostudies-arrayexpress
Project description:The plasma cell transcription factor XBP1 is critical for terminal differentiation of B cells into plasma cells but has no known role at earlier stages of B-cell development. Here we show that XBP1 is not only important during early B-cell development and for survival of pre-B cells but also protects pre-B ALL cells. Among pre-B ALL subset, XBP1 was hypomethylated and highest expressed in the Ph+ ALL subset. Cre-mediated deletion of XBP1 in a mouse model of Ph+ ALL compromised proliferation and viability and prolonged survival of leukemia-bearing mice. Interestingly, XBP1 expression levels were positively transcriptionally regulated by STAT5 and negatively by BACH2 and BCL6. High XBP1 expression in high risk ALL patients at the time of diagnosis predicted poor outcome in two clinical trials. Clinically, small-molecule inhibition of IRE1-dependent XBP1-activation caused cell death of patient-derived pre-B ALL cells and affected leukemia-initiation in transplant recipient mice. Collectively, these studies identify XBP1 as an important survival factor and as a potential therapeutic target to overcome drug-resistance in pre-B ALL. Genome-wide profiling of mRNA levels in p210 transduced murine Xbp1 fl/+ pre-B cells with ERT2 (XE.1,2,3) and Cre- ERT2 M-BM- (XC.1,2,3).
2014-04-24 | E-GEOD-53683 | biostudies-arrayexpress
Project description:The plasma cell transcription factor XBP1 is critical for terminal differentiation of B cells into plasma cells but has no known role at earlier stages of B-cell development. Here we show that XBP1 is not only important during early B-cell development and for survival of pre-B cells but also protects pre-B ALL cells. Among pre-B ALL subset, XBP1 was hypomethylated and highest expressed in the Ph+ ALL subset. Cre-mediated deletion of XBP1 in a mouse model of Ph+ ALL compromised proliferation and viability and prolonged survival of leukemia-bearing mice. Interestingly, XBP1 expression levels were positively transcriptionally regulated by STAT5 and negatively by BACH2 and BCL6. High XBP1 expression in high risk ALL patients at the time of diagnosis predicted poor outcome in two clinical trials. Clinically, small-molecule inhibition of IRE1-dependent XBP1-activation caused cell death of patient-derived pre-B ALL cells and affected leukemia-initiation in transplant recipient mice. Collectively, these studies identify XBP1 as an important survival factor and as a potential therapeutic target to overcome drug-resistance in pre-B ALL. Genome-wide profiling of mRNA levels in BCR-ABL1 transduced murine Grp78 fl/fl pre-B cells with an empty vector (Grp78 wild type, MIG-1,2,3) and Cre (Grp78 deletion, CRE-1,2,3).
2014-04-24 | E-GEOD-53684 | biostudies-arrayexpress
Project description:The plasma cell transcription factor XBP1 is critical for terminal differentiation of B cells into plasma cells but has no known role at earlier stages of B-cell development. Here we show that XBP1 is not only important during early B-cell development and for survival of pre-B cells but also protects pre-B ALL cells. Among pre-B ALL subset, XBP1 was hypomethylated and highest expressed in the Ph+ ALL subset. Cre-mediated deletion of XBP1 in a mouse model of Ph+ ALL compromised proliferation and viability and prolonged survival of leukemia-bearing mice. Interestingly, XBP1 expression levels were positively transcriptionally regulated by STAT5 and negatively by BACH2 and BCL6. High XBP1 expression in high risk ALL patients at the time of diagnosis predicted poor outcome in two clinical trials. Clinically, small-molecule inhibition of IRE1-dependent XBP1-activation caused cell death of patient-derived pre-B ALL cells and affected leukemia-initiation in transplant recipient mice. Collectively, these studies identify XBP1 as an important survival factor and as a potential therapeutic target to overcome drug-resistance in pre-B ALL.
2014-04-24 | GSE53684 | GEO
Project description:The plasma cell transcription factor XBP1 is critical for terminal differentiation of B cells into plasma cells but has no known role at earlier stages of B-cell development. Here we show that XBP1 is not only important during early B-cell development and for survival of pre-B cells but also protects pre-B ALL cells. Among pre-B ALL subset, XBP1 was hypomethylated and highest expressed in the Ph+ ALL subset. Cre-mediated deletion of XBP1 in a mouse model of Ph+ ALL compromised proliferation and viability and prolonged survival of leukemia-bearing mice. Interestingly, XBP1 expression levels were positively transcriptionally regulated by STAT5 and negatively by BACH2 and BCL6. High XBP1 expression in high risk ALL patients at the time of diagnosis predicted poor outcome in two clinical trials. Clinically, small-molecule inhibition of IRE1-dependent XBP1-activation caused cell death of patient-derived pre-B ALL cells and affected leukemia-initiation in transplant recipient mice. Collectively, these studies identify XBP1 as an important survival factor and as a potential therapeutic target to overcome drug-resistance in pre-B ALL.
2014-04-24 | GSE53683 | GEO
Project description:Inhibitors of B-cell receptor (BCR) and pre-BCR signaling were successfully introduced into patient care for various subtypes of mature B-cell lymphoma (e.g., ibrutinib, idelalisib). Acute lymphoblastic leukemia (ALL) typically originates from pre-B cells that critically depend on survival signals emanating from a functional pre-BCR. However, whether patients with ALL benefit from treatment with (pre-) BCR inhibitors has not been explored. Recent data suggest that the pre-BCR functions as tumor suppressor in the majority of cases of human ALL. However, a distinct subset of human ALL is selectively sensitive to pre-BCR antagonists.
| S-EPMC4463734 | biostudies-literature
Project description:Chromosomal rearrangements of the mixed lineage leukemia (MLL) gene occur in ∼10% of B-cell acute lymphoblastic leukemia (B-ALL) and define a group of patients with dismal outcomes. Immunohistochemical staining of bone marrow biopsies from most of these patients revealed aberrant expression of BCL6, a transcription factor that promotes oncogenic B-cell transformation and drug resistance in B-ALL. Our genetic and ChIP-seq (chromatin immunoprecipitation [ChIP] combined with high-throughput sequencing) analyses showed that MLL-AF4 and MLL-ENL fusions directly bound to the BCL6 promoter and up-regulated BCL6 expression. While oncogenic MLL fusions strongly induced aberrant BCL6 expression in B-ALL cells, germline MLL was required to up-regulate Bcl6 in response to physiological stimuli during normal B-cell development. Inducible expression of Bcl6 increased MLL mRNA levels, which was reversed by genetic deletion and pharmacological inhibition of Bcl6, suggesting a positive feedback loop between MLL and BCL6. Highlighting the central role of BCL6 in MLL-rearranged B-ALL, conditional deletion and pharmacological inhibition of BCL6 compromised leukemogenesis in transplant recipient mice and restored sensitivity to vincristine chemotherapy in MLL-rearranged B-ALL patient samples. Oncogenic MLL fusions strongly induced transcriptional activation of the proapoptotic BH3-only molecule BIM, while BCL6 was required to curb MLL-induced expression of BIM. Notably, peptide (RI-BPI) and small molecule (FX1) BCL6 inhibitors derepressed BIM and synergized with the BH3-mimetic ABT-199 in eradicating MLL-rearranged B-ALL cells. These findings uncover MLL-dependent transcriptional activation of BCL6 as a previously unrecognized requirement of malignant transformation by oncogenic MLL fusions and identified BCL6 as a novel target for the treatment of MLL-rearranged B-ALL.
| S-EPMC6719625 | biostudies-literature
Project description:Acute Lymphoblastic Leukemia (ALL) is an aggressive hematologic disorder and constitutes approximately 25% of cancer diagnoses among children and teenagers. Pediatric patients have a favourable prognosis, with 5-years overall survival rates near 90%, while adult ALL still correlates with poorer survival. However, during the past few decades, the therapeutic outcome of adult ALL was significantly ameliorated, mainly due to intensive pediatric-based protocols of chemotherapy. Mammalian (or mechanistic) target of rapamycin (mTOR) is a conserved serine/threonine kinase belonging to the phosphatidylinositol 3-kinase (PI3K)-related kinase family (PIKK) and resides in two distinct signalling complexes named mTORC1, involved in mRNA translation and protein synthesis and mTORC2 that controls cell survival and migration. Moreover, both complexes are remarkably involved in metabolism regulation. Growing evidence reports that mTOR dysregulation is related to metastatic potential, cell proliferation and angiogenesis and given that PI3K/Akt/mTOR network activation is often associated with poor prognosis and chemoresistance in ALL, there is a constant need to discover novel inhibitors for ALL treatment. Here, the current knowledge of mTOR signalling and the development of anti-mTOR compounds are documented, reporting the most relevant results from both preclinical and clinical studies in ALL that have contributed significantly into their efficacy or failure.
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Project description:Adhesion of acute lymphoblastic leukemia (ALL) cells to bone marrow stroma cells triggers intracellular signals regulating cell-adhesion-mediated drug resistance (CAM-DR). Stromal cell protection of ALL cells has been shown to require active AKT. In chronic lymphocytic leukemia (CLL), adhesion-mediated activation of the PI3K/AKT pathway is reported. A novel FDA-approved PI3K? inhibitor, CAL-101/idelalisib, leads to downregulation of p-AKT and increased apoptosis of CLL cells. Recently, two additional PI3K inhibitors have received FDA approval. As the PI3K/AKT pathway is also implicated in adhesion-mediated survival of ALL cells, PI3K inhibitors have been evaluated preclinically in ALL. However, PI3K inhibition has yet to be approved for clinical use in ALL. Here, we review the role of PI3K in normal hematopoietic cells, and in ALL. We focus on summarizing targeting strategies of PI3K in ALL.
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