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Cytotoxic effects of Bortezomib in Myelodysplastic syndrome/Acute Myeloid Leukemia depend on autophagy-mediated lysosomal degradation of TRAF6 and repression of PSMA1

ABSTRACT: Bortezomib (Velcade©) is widely used for the treatment of various human cancers, however, its mechanisms of action are not fully understood, particularly in myeloid malignancies. Bortezomib is a selective and reversible inhibitor of the proteasome. Paradoxically, we find that Bortezomib induces proteasome-independent degradation of TRAF6 protein, but not mRNA, in Myelodysplastic syndrome (MDS) and Acute Myeloid Leukemia (AML) cell lines and primary cells. The reduction in TRAF6 protein coincides with Bortezomib-induced autophagy, and subsequently with apoptosis in MDS/AML cells. RNAi-mediated knockdown of TRAF6 sensitized Bortezomib-sensitive and -resistant cell lines, underscoring the importance of TRAF6 in Bortezomib-induced cytotoxicity. Bortezomib-resistant cells expressing an shRNA targeting TRAF6 were resensitized to the cytotoxic effects of Bortezomib due to down-regulation of the proteasomal subunit alpha-1 (PSMA1). To uncover the molecular consequences following loss of TRAF6 in MDS/AML cells, we applied gene expression profiling and identified an apoptosis gene signature. Knockdown of TRAF6 in MDS/AML cell lines or patient samples resulted in rapid apoptosis and impaired malignant hematopoietic stem/progenitor function. In summary, we describe novel mechanisms by which TRAF6 is regulated through Bortezomib/autophagy-mediated degradation and by which it alters MDS/AML sensitivity to Bortezomib by controlling PSMA1 expression.

ORGANISM(S): Homo sapiens

PROVIDER: GSE38519 | GEO | 2012/06/15

SECONDARY ACCESSION(S): PRJNA168095

REPOSITORIES: GEO

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Cytotoxic effects of Bortezomib in Myelodysplastic syndrome/Acute Myeloid Leukemia depend on autophagy-mediated lysosomal degradation of TRAF6 and repression of PSMA1

Project description:Bortezomib (VelcadeM-BM-)) is widely used for the treatment of various human cancers, however, its mechanisms of action are not fully understood, particularly in myeloid malignancies. Bortezomib is a selective and reversible inhibitor of the proteasome. Paradoxically, we find that Bortezomib induces proteasome-independent degradation of TRAF6 protein, but not mRNA, in Myelodysplastic syndrome (MDS) and Acute Myeloid Leukemia (AML) cell lines and primary cells. The reduction in TRAF6 protein coincides with Bortezomib-induced autophagy, and subsequently with apoptosis in MDS/AML cells. RNAi-mediated knockdown of TRAF6 sensitized Bortezomib-sensitive and -resistant cell lines, underscoring the importance of TRAF6 in Bortezomib-induced cytotoxicity. Bortezomib-resistant cells expressing an shRNA targeting TRAF6 were resensitized to the cytotoxic effects of Bortezomib due to down-regulation of the proteasomal subunit alpha-1 (PSMA1). To uncover the molecular consequences following loss of TRAF6 in MDS/AML cells, we applied gene expression profiling and identified an apoptosis gene signature. Knockdown of TRAF6 in MDS/AML cell lines or patient samples resulted in rapid apoptosis and impaired malignant hematopoietic stem/progenitor function. In summary, we describe novel mechanisms by which TRAF6 is regulated through Bortezomib/autophagy-mediated degradation and by which it alters MDS/AML sensitivity to Bortezomib by controlling PSMA1 expression. TF-1 cells were transduced with lentivirus encoding shRNA targeting human TRAF6 and a negative control (pLKO) for 2.5 days. GFP positive cells were sorted for RNA exctration, labeling, and hybridization. A total of four samples were included, and two groups are assigned. Two replicates are for each group. Comparison comprises mRNA expression profile of TRAF6 knockdown (shT6) v.s. control vector (pLKO).

2012-06-14 | E-GEOD-38519 | biostudies-arrayexpress

Bortezomib suppresses self-renewal and leukemogenesis of leukemia stem cell by NF-ĸB-dependent inhibition of cyclin dependent kinase 6 in MLL-rearranged myeloid leukemia

Project description:Acute myeloid leukemia (AML) with chromosomal rearrangements involving the H3K4 methyltransferase mixed-lineage leukemia (MLL) is an aggressive subtype with low overall survival. MLL rearrangements rapidly transform hematological stem and progenitor cell (HSPC) to leukemia stem cell (LSC). Bortezomib (Velcade) is used widely in hematological malignancies. However, it is still unknown whether bortezomib possesses anti-self-renewal and anti-leukemogenesis of LSC in AML with MLL rearrangements. Here, we found that bortezomib inhibited cell proliferation, induced apoptosis, and decreased colony formation in leukemic cell lines, primary AML blasts, and MLL-AF9-transformed murine leukemic blasts. Besides, bortezomib reduced the frequency and function of LSC, inhibited the progression, and prolonged

2022-08-10 | GSE157702 | GEO

Myeloid malignancies with chromosome 5q deletions acquire a dependency on an intrachromosomal NF-M-NM-:B gene network

Project description:Chromosome 5q deletions (del(5q)) are common in high-risk (HR) Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML); however, the gene regulatory networks that sustain these aggressive diseases are unknown. Reduced miR-146a expression in del(5q) HR-MDS/AML and miR-146a-/- hematopoietic stem/progenitor cells (HSPC) results in TRAF6/NF-M-NM-:M-NM-^R activation. Increased survival and proliferation of HSPC from miR-146alow HR-MDS/AML is sustained by a neighboring haploid gene, SQSTM1 (p62), expressed from the intact 5q allele. Overexpression of p62 from the intact allele occurs through NF-M-NM-:B-dependent feedforward signaling mediated by miR-146a deficiency. p62 is necessary for TRAF6-mediated NF-M-NM-:B signaling, as disrupting the p62-TRAF6 signaling complex results in cell cycle arrest and apoptosis of MDS/AML cells. Thus, del(5q) HR-MDS/AML employs an intrachromosomal gene network involving loss of miR-146a and haploid overexpression of p62 via NF-M-NM-:B to sustain TRAF6/NF-M-NM-:B signaling for cell survival and proliferation. Interfering with the p62-TRAF6 signaling complex represents a therapeutic option in miR-146a-deficient and aggressive del(5q) MDS/AML. Four del(5q) MDS/AML patients with low miR-146a expression (5284, 8839, 8285, 4233) and 5 with high miR-146a expression (7957, 5534, 4688, 4982, 8412) were selected for microarray assay. RNA was reverse transcribed and labeled, and hybridized onto the GeneChip Human Gene 1.0 ST Array. A total of nine samples were included, and two groups are assigned based on miR-146a expression. Comparison comprises mRNA expression profile of low miR-146a group v.s. high miR-146a group.

2014-08-23 | E-GEOD-60649 | biostudies-arrayexpress

Myeloid malignancies with chromosome 5q deletions acquire a dependency on an intrachromosomal NF-κB gene network

Project description:Chromosome 5q deletions (del(5q)) are common in high-risk (HR) Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML); however, the gene regulatory networks that sustain these aggressive diseases are unknown. Reduced miR-146a expression in del(5q) HR-MDS/AML and miR-146a-/- hematopoietic stem/progenitor cells (HSPC) results in TRAF6/NF-κΒ activation. Increased survival and proliferation of HSPC from miR-146alow HR-MDS/AML is sustained by a neighboring haploid gene, SQSTM1 (p62), expressed from the intact 5q allele. Overexpression of p62 from the intact allele occurs through NF-κB-dependent feedforward signaling mediated by miR-146a deficiency. p62 is necessary for TRAF6-mediated NF-κB signaling, as disrupting the p62-TRAF6 signaling complex results in cell cycle arrest and apoptosis of MDS/AML cells. Thus, del(5q) HR-MDS/AML employs an intrachromosomal gene network involving loss of miR-146a and haploid overexpression of p62 via NF-κB to sustain TRAF6/NF-κB signaling for cell survival and proliferation. Interfering with the p62-TRAF6 signaling complex represents a therapeutic option in miR-146a-deficient and aggressive del(5q) MDS/AML.

2014-08-23 | GSE60649 | GEO

Genome-wide analysis of gene expression in response to bortezomib treatment [mouse cell lines II]

Project description:Genome-wide analysis of gene expression in response to bortezomib treatment(33 nM) in cell lines before and after selection for resistance. Multiple myeloma (MM) is a hematologic malignancy characterized by the proliferation of neoplastic plasma cells in the bone marrow. While the first-to-market proteasome inhibitor bortezomib/VELCADE has been successfully used to treat myeloma patients, drug resistance remains an emerging problem. In this study, we identify signatures of bortezomib sensitivity and resistance by gene expression profiling (GEP) using pairs of bortezomib-sensitive and -resistant cell lines created from the Bcl-XL/Myc double transgenic mouse model of MM. Finally, these data reveal complex heterogeneity within MM and suggest resistance to one drug class reprograms resistant clones to make them more sensitive to a distinct class of drugs. This study represents an important next step in translating pharmacogenomic profiling and may be useful for understanding personalized pharmacotherapy of MM patients. Transcript profiling timecourses after treatment with Bortezomib treatment (33nm) in Multiple Myeloma derived cell lines.

2013-07-02 | E-GEOD-41928 | biostudies-arrayexpress

Genome-wide analysis of gene expression in response to bortezomib treatment [mouse cell lines I]

Project description:Genome-wide analysis of gene expression in response to bortezomib treatment (33 nM) in cell lines before and after selection for resistance. Multiple myeloma (MM) is a hematologic malignancy characterized by the proliferation of neoplastic plasma cells in the bone marrow. While the first-to-market proteasome inhibitor bortezomib/VELCADE has been successfully used to treat myeloma patients, drug resistance remains an emerging problem. In this study, we identify signatures of bortezomib sensitivity and resistance by gene expression profiling (GEP) using pairs of bortezomib-sensitive and -resistant cell lines created from the Bcl-XL/Myc double transgenic mouse model of MM. Finally, these data reveal complex heterogeneity within MM and suggest resistance to one drug class reprograms resistant clones to make them more sensitive to a distinct class of drugs. This study represents an important next step in translating pharmacogenomic profiling and may be useful for understanding personalized pharmacotherapy of MM patients. Transcript profiling timecourses after treatment with Bortezomib treatment (33nm) in Multiple Myeloma derived cell lines.

2013-07-02 | E-GEOD-41927 | biostudies-arrayexpress

Genome-wide analysis of gene expression in response to bortezomib treatment [human cell lines].

Project description:Genome-wide analysis of gene expression in response to bortezomib treatment (33 nM) in cell lines before and after selection for resistance. Multiple myeloma (MM) is a hematologic malignancy characterized by the proliferation of neoplastic plasma cells in the bone marrow. While the first-to-market proteasome inhibitor bortezomib/VELCADE has been successfully used to treat myeloma patients, drug resistance remains an emerging problem. In this part of the study, we identify signatures of bortezomib sensitivity by gene expression profiling (GEP) using The human myeloma cell lines MM1.S and U266 (obtained from ATCC). Finally, these data reveal complex heterogeneity within MM and suggest resistance to one drug class reprograms resistant clones to make them more sensitive to a distinct class of drugs. This study represents an important next step in translating pharmacogenomic profiling and may be useful for understanding personalized pharmacotherapy of MM patients. Transcript profiling timecourses after treatment with Bortezomib treatment (33nm) in two myeloma cell lines.

2013-07-02 | E-GEOD-41929 | biostudies-arrayexpress

Proteasome inhibition blocks estrogen-dependent gene transcription by decreasing histone H2B monoubiquitination in human breast cancer cells

Project description:The estrogen receptor-alpha (ERα) determines breast cancer cell phenotype and is a prognostic indicator. A better understanding of the mechanisms controlling ERα function may uncover improved strategies for the treatment of breast cancer. Proteasome inhibition was previously reported to regulate estrogen-induced transcription but the mechanisms by which it influences ERα function remain controversial. In this study we investigated the transcriptome-wide effects of the proteasome inhibitor Velcade on estrogen-regulated transcription in MCF7 human breast cancer cells and demonstrate a specific global decrease in estrogen-induced transcription. This set contains 12 microarray samples. 3 controls, 3 estrogen stimulated, 3 Bortezomib stimulated, 3 Bortezomib + estrogen stimulated

2011-11-22 | E-GEOD-30931 | biostudies-arrayexpress

Genome-wide analysis of gene expression in response to bortezomib treatment [mouse cell lines I]

Project description:Genome-wide analysis of gene expression in response to bortezomib treatment (33 nM) in cell lines before and after selection for resistance. Multiple myeloma (MM) is a hematologic malignancy characterized by the proliferation of neoplastic plasma cells in the bone marrow. While the first-to-market proteasome inhibitor bortezomib/VELCADE has been successfully used to treat myeloma patients, drug resistance remains an emerging problem. In this study, we identify signatures of bortezomib sensitivity and resistance by gene expression profiling (GEP) using pairs of bortezomib-sensitive and -resistant cell lines created from the Bcl-XL/Myc double transgenic mouse model of MM. Finally, these data reveal complex heterogeneity within MM and suggest resistance to one drug class reprograms resistant clones to make them more sensitive to a distinct class of drugs. This study represents an important next step in translating pharmacogenomic profiling and may be useful for understanding personalized pharmacotherapy of MM patients.

2013-07-02 | GSE41927 | GEO

Genome-wide analysis of gene expression in response to bortezomib treatment [mouse cell lines II]

2013-07-02 | GSE41928 | GEO

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