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

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

PROVIDER: PRJNA778528 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR16842797_1.fastq.gz	Fastqsanger.gz
	SRR16842797_2.fastq.gz	Fastqsanger.gz
	SRR16842798_1.fastq.gz	Fastqsanger.gz
	SRR16842798_2.fastq.gz	Fastqsanger.gz

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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

Targeting the RBM39-MEK5 axis synergizes with bortezomib to inhibit the malignant growth of multiple myeloma

Project description:Targeting the RBM39-MEK5 axis synergizes with bortezomib to inhibit the malignant growth of multiple myeloma

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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

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

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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

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TET2 lesions enhance the aggressiveness of CEBPA-mutant AML by rebalancing GATA2 expression [WGBS]

Project description:The myeloid transcription factor CEBPA is recurrently biallelically mutated (i.e., double mutated; CEBPADM) in acute myeloid leukemia (AML) with a combination of hypermorphic N-terminal mutations (CEBPANT), promoting expression of the leukemia-associated p30 isoform, and amorphic C-terminal mutations. CEBPADM AML features recurrent co-occurring mutations including GATA2 lesions, however insights into mechanisms governing this co-mutational spectrum are incomplete. By combining transcriptomic and epigenomic analyses of CEBPA-TET2 co-mutated patients with models thereof, we identify GATA2 as a conserved target of the CEBPA-TET2 mutational axis, providing a rationale for the mutational spectra in CEBPADM AML. Mechanistically, we suggest that elevated CEBPA levels, driven by CEBPANT, mediate recruitment of TET2 to the Gata2 distal hematopoietic enhancer thereby increasing Gata2 expression. Conversely, CEBPADM AML gains a competitive advantage through TET2 loss, by decreasing Gata2 promoter demethylation thereby rebalancing GATA2 levels. Of clinical relevance, demethylating treatment of Cebpa-Tet2 co-mutated AML restores Gata2 levels and prolongs disease latency.

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RNA-seq of murine MA9 Gata2 f/f and Gata2 -/- (Gata2 KO) leukemias with Nutlin

Project description:Transcriptional effects of Nutlin treatment in murine MA9 leukemia after loss of Gata2.

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TET2 lesions enhance the aggressiveness of CEBPA-mutant AML by rebalancing GATA2 expression [RNA-Seq]

2023-08-28 | GSE213821 | GEO

TET2 lesions enhance the aggressiveness of CEBPA-mutant AML by re-balancing GATA2 expression

Project description:The myeloid transcription factor CEBPA is recurrently biallelically mutated (i.e., double mutated; CEBPADM) in acute myeloid leukemia (AML); with a combination of hypermorphic N-terminal mutations (CEBPANT), promoting expression of the leukemia-associated p30 isoform, and amorphic C-terminal mutations. CEBPADM AML features recurrent co‑occurring mutations; however, insight into the underlying mechanisms for the co-mutational spectra is incomplete. By combining transcriptomic and epigenomic analyses of data from CEBPA-TET2-co-mutant patients with experimental models thereof, we identify GATA2 as a conserved target of the CEBPA-TET2 mutational axis, providing a rationale for the mutational spectra in CEBPADM AML. Mechanistically, we suggest that elevated CEBPA levels, driven by the CEBPANT, mediate recruitment of TET2 to the GATA2 distal hematopoietic enhancer and thereby increase GATA2 expression. Conversely, CEBPADM AML gains a competitive advantage by loss of TET2; decreasing GATA2 promoter demethylation and re-balancing GATA2 levels. Further, demethylating treatment of CEBPA-TET2-co-mutant AML restores GATA2 levels, and prolongs disease latency.

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