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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

ABSTRACT: 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

PROVIDER: PRJNA662502 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR12615657_1.fastq.gz	Fastqsanger.gz
	SRR12615657_2.fastq.gz	Fastqsanger.gz
	SRR12615658_1.fastq.gz	Fastqsanger.gz
	SRR12615658_2.fastq.gz	Fastqsanger.gz

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Similar Datasets

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

Bortezomib suppresses self-renewal and leukemogenesis of leukemia stem cell by NF-ĸB-dependent inhibition of CDK6 in MLL-rearranged myeloid leukemia.

Project description:Acute myeloid leukaemia (AML) with chromosomal rearrangements involving the H3K4 methyltransferase mixed-lineage leukaemia (MLL) is an aggressive subtype with low overall survival. Bortezomib (Bort) is first applied in multiple myeloma. However, whether bort possesses anti-self-renewal and leukemogenesis of leukaemia stem cell (LSC) in AML with MLL rearrangements is still unclear. Here, we found that bort suppressed cell proliferation and decreased colony formation in human and murine leukaemic blasts. Besides, bort reduced the frequency and function of LSC, inhibited the progression, and extended the overall survival in MLL-AF9 (MF9) -transformed leukaemic mice. Furthermore, bort decreased the percentage of human LSC (CD34+ CD38- ) cells and extended the overall survival in AML blasts-xenografted NOD/SCID-IL2Rγ (NSG) mice. Mechanistically, cyclin dependent kinase 6 (CDK6) was identified as a bort target by RNA sequencing. Bort reduced the expressions of CDK6 by inhibiting NF ĸB recruitment to the promoter of CDK6, leading to the abolishment of NF ĸB DNA-binding activity for CDK6 promoter. Overexpression of CDK6 partially rescued bort-induced anti-leukemogenesis. Most importantly, bort had little side-effect against the normal haematological stem and progenitor cell (HSPC) and did not affect CDK6 expression in normal HSPC. In conclusion, our results suggest that bort selectively targets LSC in MLL rearrangements. Bort might be a prospective drug for AML patients bearing MLL rearrangements.

| S-EPMC7957264 | biostudies-literature

Anti-leukemia activity of bortezomib through GATA2-WT1 axis in acute myeloid leukemia

Project description:GATA2 is a transcription factor essential for hematopoietic differentiation and lymphatic system formation. High expression of GATA2 has been implicated in myelodysplastic syndrome and acute myeloid leukemia. Bortezomib has a good effect in MM. However, the mechanism of bortezomib possesses anti-self-renewal and leukemogenesis in AML is still unclear. Here, we reported that GATA2 and WT1 protein is degraded by bortezomib. The half-life of GATA2 mRNA was obviously shorter in Bortezomib-treated cells. Knockdown of GATA2 by small hairpin RNAs (shRNAs) has potential anti-leukemia activity in leukemic cells. Bortezomib inhibited cell proliferation and induced apoptotic death without activation of caspases pathway. Finally, bortezomib decreased xenograft tumor size in a xenograft leukemia mouse model, and prolonged the survival time in mouse C1498 AML model. Collectively, bortezomib might be a potential treatment for AML.

2021-11-14 | GSE188358 | GEO

Molecular targets of bortezomib on adult T-cell leukemia cells

Project description:BACKGROUND: The molecular mechanism of proteasome inhibitor-mediated anti-cancer activity has been logically hypothesized that the major pathway is inhibition of nuclear factor kappa-B (NF-kB) cascades, however, the precise mechanism is still unclear. Adult T-cell leukemia (ATL) is a fatal neoplasia derived from HTLV-1 infected T lymphocytes exhibiting constitutive activation of NF-kB. AIM: To elucidate the complex molecular mechanism of anti-tumor effect of the proteasome inhibitor, bortezomib in ATL cells, we attempted to perform network-based gene expression profiling. METHODS and RESULTS: Assessment of gene regulation by microarray analysis revealed that down-regulation of genes involved in anti-apoptosis (i.e., BCL2, and IAP5), up-regulation of genes related with apoptosis (i.e., FAF1), heat shock proteins (i.e., HSPA, HSPCA), and oxygen stress (i.e., heme oxygenase-1: HMOX-1). Gene network analysis employing the Bayesian statistical framework also suggests that HMOX-1 which is known as an inducer of reactive oxygen species (ROS), as well as SPARC play an important role in bortezomib-treated ATL cells. The HMOX-1 inhibitor, ZnPP, in addition to bortezomib partially inhibited the apoptotic effect of bortezomib on TaY cells. CONCLUSION: Our results suggest that in addition to the inhibition of NF-kB, bortezomib activated ROS pathway through HMOX-1, and SPARC may participate bortezomib-induced apoptosis, providing novel insight into the bortezomib mediated anti-tumor activity in ATL cells. Keywords: dose response and time course

2007-10-09 | GSE5794 | GEO

Anti-leukemia activity of bortezomib through GATA2-WT1 axis in acute myeloid leukemia

Project description:Anti-leukemia activity of bortezomib through GATA2-WT1 axis in acute myeloid leukemia

| PRJNA778528 | ENA

Transcription profiling of four human Adult T-cell leukemia (ATL) cell lines treated with proteasome inhibitor, bortezomib

Project description:Adult T-cell leukemia (ATL) is a fatal neoplasia derived from HTLV-1 infected T lymphocytes exhibiting constitutive activation of NF-kB. To elucidate the complex molecular mechanism of anti-tumor effect of the proteasome inhibitor, bortezomib in ATL cells, we attempted to perform gene expression profiling. Experiment Overall Design: Four ATL cell lines were cultured with or without bortezomib, then analysed.

2008-06-14 | E-GEOD-6034 | biostudies-arrayexpress

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 (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.

2012-06-15 | GSE38519 | GEO

FGFR inhibition blocks NF-ĸB-dependent glucose metabolism and confers metabolic vulnerabilities in cholangiocarcinoma

Project description:FGFR inhibition blocks NF-ĸB-dependent glucose metabolism and confers metabolic vulnerabilities in cholangiocarcinoma

| PRJNA1009431 | ENA

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

A Subset of Genes Can Distinguish between Bortezomib Responsive Versus Bortezomib Resistant Myeloma

Project description:Gene expression profile (GEP) was analyzed from cultured bone marrow (BM) samples from patients with bortezomib responsive versus bortezomib resistant myeloma after 6-8 hours incubation in vitro with bortezomib 2 µg/ml or with PBS. Case D also had a fresh BM sample taken 75 minutes after IV injection of bortezomib.

2013-11-01 | GSE51940 | GEO

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