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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]

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE138384 | GEO | 2020/07/02

REPOSITORIES: GEO

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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]

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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

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-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 [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 RNA-seq]

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