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Combined Inhibition of JAK/STAT Pathway and Lysine Demethylase 1 as a Novel Therapeutic Strategy in CSF3R/CEBPA Mutant Acute Myeloid Leukemia

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE138388 | GEO | 2020/07/02

REPOSITORIES: GEO

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Combined inhibition of JAK/STAT pathway and lysine-specific demethylase 1 as a therapeutic strategy in CSF3R/CEBPA mutant acute myeloid leukemia.

Project description:Acute myeloid leukemia (AML) is a deadly hematologic malignancy with poor prognosis, particularly in the elderly. Even among individuals with favorable-risk disease, approximately half will relapse with conventional therapy. In this clinical circumstance, the determinants of relapse are unclear, and there are no therapeutic interventions that can prevent recurrent disease. Mutations in the transcription factor CEBPA are associated with favorable risk in AML. However, mutations in the growth factor receptor CSF3R are commonly co-occurrent in CEBPA mutant AML and are associated with an increased risk of relapse. To develop therapeutic strategies for this disease subset, we performed medium-throughput drug screening on CEBPA/CSF3R mutant leukemia cells and identified sensitivity to inhibitors of lysine-specific demethylase 1 (LSD1). Treatment of CSF3R/CEBPA mutant leukemia cells with LSD1 inhibitors reactivates differentiation-associated enhancers driving immunophenotypic and morphologic differentiation. LSD1 inhibition is ineffective as monotherapy but demonstrates synergy with inhibitors of JAK/STAT signaling, doubling median survival in vivo. These results demonstrate that combined inhibition of JAK/STAT signaling and LSD1 is a promising therapeutic strategy for CEBPA/CSF3R mutant AML.

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Combined Inhibition of JAK/STAT Pathway and Lysine Demethylase 1 as a Novel Therapeutic Strategy in CSF3R/CEBPA Mutant Acute Myeloid Leukemia [LSD1i ChIP-seq]

Project description:The presence of CSF3R mutations are associated with adverse outcomes in CEBPA mutant AML. Here we report that inhibitors of LSD1 reverse the mutant CEBPA-mediated differentiation blockade and exhibit synergy with JAK/STAT inhibitors.

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Combined Inhibition of JAK/STAT Pathway and Lysine Demethylase 1 as a Novel Therapeutic Strategy in CSF3R/CEBPA Mutant Acute Myeloid Leukemia [RUX_GSK RNA-seq]

2020-07-02 | GSE138386 | GEO

Combined Inhibition of JAK/STAT Pathway and Lysine Demethylase 1 as a Novel Therapeutic Strategy in CSF3R/CEBPA Mutant Acute Myeloid Leukemia [LSD1i RNA-seq]

2020-07-02 | GSE138384 | GEO

Combined Inhibition of JAK/STAT Pathway and Lysine Demethylase 1 as a Novel Therapeutic Strategy in CSF3R/CEBPA Mutant Acute Myeloid Leukemia

Project description:Combined Inhibition of JAK/STAT Pathway and Lysine Demethylase 1 as a Novel Therapeutic Strategy in CSF3R/CEBPA Mutant Acute Myeloid Leukemia

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Combined Inhibition of JAK/STAT Pathway and Lysine Demethylase 1 as a Novel Therapeutic Strategy in CSF3R/CEBPA Mutant Acute Myeloid Leukemia [LSD1i RNA-seq]

Project description:Combined Inhibition of JAK/STAT Pathway and Lysine Demethylase 1 as a Novel Therapeutic Strategy in CSF3R/CEBPA Mutant Acute Myeloid Leukemia [LSD1i RNA-seq]

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Combined Inhibition of JAK/STAT Pathway and Lysine Demethylase 1 as a Novel Therapeutic Strategy in CSF3R/CEBPA Mutant Acute Myeloid Leukemia [RUX_GSK RNA-seq]

Project description:Combined Inhibition of JAK/STAT Pathway and Lysine Demethylase 1 as a Novel Therapeutic Strategy in CSF3R/CEBPA Mutant Acute Myeloid Leukemia [RUX_GSK RNA-seq]

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Combined Inhibition of JAK/STAT Pathway and Lysine Demethylase 1 as a Novel Therapeutic Strategy in CSF3R/CEBPA Mutant Acute Myeloid Leukemia [LSD1i ChIP-seq]

Project description:Combined Inhibition of JAK/STAT Pathway and Lysine Demethylase 1 as a Novel Therapeutic Strategy in CSF3R/CEBPA Mutant Acute Myeloid Leukemia [LSD1i ChIP-seq]

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Myeloid lineage enhancers drive oncogene synergy in CEBPA/CSF3R mutant acute myeloid leukemia.

Project description:Acute Myeloid Leukemia (AML) develops due to the acquisition of mutations from multiple functional classes. Here, we demonstrate that activating mutations in the granulocyte colony stimulating factor receptor (CSF3R), cooperate with loss of function mutations in the transcription factor CEBPA to promote acute leukemia development. The interaction between these distinct classes of mutations occurs at the level of myeloid lineage enhancers where mutant CEBPA prevents activation of a subset of differentiation associated enhancers. To confirm this enhancer-dependent mechanism, we demonstrate that CEBPA mutations must occur as the initial event in AML initiation. This improved mechanistic understanding will facilitate therapeutic development targeting the intersection of oncogene cooperativity.

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Project description:Effective therapy of acute myeloid leukemia (AML) remains an unmet need. DNA methylcytosine dioxygenase Ten-eleven translocation 1 (TET1) is a critical oncoprotein in AML. Through a series of data analysis and drug screening, we identified two compounds (i.e., NSC-311068 and NSC-370284) that selectively suppress TET1 transcription and 5-hydroxymethylcytosine (5hmC) modification, and effectively inhibit cell viability in AML with high expression of TET1 (i.e., TET1-high AML), including AML carrying t(11q23)/MLL-rearrangements and t(8;21) AML. NSC-311068 and especially NSC-370284 significantly repressed TET1-high AML progression in vivo. UC-514321, a structural analog of NSC-370284, exhibited a more potent therapeutic effect and prolonged the median survival of TET1-high AML mice over three fold. NSC-370284 and UC-514321 both directly target STAT3/5, transcriptional activators of TET1, and thus repress TET1 expression. They also exhibit strong synergistic effects with standard chemotherapy. Our results highlight the therapeutic potential of targeting the STAT/TET1 axis by selective inhibitors in AML treatment.

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