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KDM5 inhibition is a novel therapeutic strategy for the treatment of KMT2D mutant lymphomas

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

ORGANISM(S): Homo sapiens

PROVIDER: GSE153671 | GEO | 2021/06/01

REPOSITORIES: GEO

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KDM5 inhibition offers a novel therapeutic strategy for the treatment of KMT2D mutant lymphomas.

Project description:Loss-of-function mutations in KMT2D are a striking feature of germinal center (GC) lymphomas, resulting in decreased histone 3 lysine 4 (H3K4) methylation and altered gene expression. We hypothesized that inhibition of the KDM5 family, which demethylates H3K4me3/me2, would reestablish H3K4 methylation and restore the expression of genes repressed on loss of KMT2D. KDM5 inhibition increased H3K4me3 levels and caused an antiproliferative response in vitro, which was markedly greater in both endogenous and gene-edited KMT2D mutant diffuse large B-cell lymphoma cell lines, whereas tumor growth was inhibited in KMT2D mutant xenografts in vivo. KDM5 inhibition reactivated both KMT2D-dependent and -independent genes, resulting in diminished B-cell signaling and altered expression of B-cell lymphoma 2 (BCL2) family members, including BCL2 itself. KDM5 inhibition may offer an effective therapeutic strategy for ameliorating KMT2D loss-of-function mutations in GC lymphomas.

| S-EPMC8351530 | biostudies-literature

KDM5 inhibition is a novel therapeutic strategy for the treatment of KMT2D mutant lymphomas [1]

Project description:Loss of function mutations within KMT2D are a striking feature of the germinal centre lymphomas, with lesions present in 80% of Follicular Lymphoma (FL) and 30% of Diffuse Large B-cell Lymphoma (DLBCL), resulting in decreased H3K4 methylation and altered gene expression. The KDM5 family normally maintains homeostasis through demethylating H3K4me3/2, thus negatively regulating gene expression. We hypothesised that inhibition of KDM5 may re-establish H3K4 methylation and restore the expression of genes repressed upon loss of KMT2D. Using a selective inhibitor of the KDM5 family we were able to increase H3K4me3 levels in DLBCL cell lines, predominantly at gene promoters, ultimately leading to decreased proliferation and cell death in KMT2D mutant cell lines. This appeared to be driven by an increase in the expression of negative regulators of B cell survival pathways, many of which have previously been described as targets of KMT2D and CREBBP, resulting in diminished BCR signalling. We also observed decreased BCL2 expression in all examined t(14;18) positive cell lines, alongside changes in other BCL2 family members in sensitive cell lines. KDM5 sensitivity was confirmed to be dependent on the presence of KMT2D mutations by generating de novo KMT2D mutant cell lines and correcting naturally mutant cell lines, which displayed greater and lesser sensitivity to KDM5 inhibition respectively. KDM5 inhibition may therefore be an effective therapeutic strategy for ameliorating KMT2D loss of function mutations in malignancies such as germinal centre lymphomas.

2021-06-01 | GSE114492 | GEO

KDM5 inhibition is a novel therapeutic strategy for the treatment of KMT2D mutant lymphomas [2]

2021-06-01 | GSE152642 | GEO

KDM5 inhibition is a novel therapeutic strategy for the treatment of KMT2D mutant lymphomas

Project description:KDM5 inhibition is a novel therapeutic strategy for the treatment of KMT2D mutant lymphomas

| PRJNA643585 | ENA

KDM5 inhibition is a novel therapeutic strategy for the treatment of KMT2D mutant lymphomas [1]

Project description:KDM5 inhibition is a novel therapeutic strategy for the treatment of KMT2D mutant lymphomas [1]

| PRJNA471534 | ENA

KDM5 inhibition is a novel therapeutic strategy for the treatment of KMT2D mutant lymphomas [2]

Project description:KDM5 inhibition is a novel therapeutic strategy for the treatment of KMT2D mutant lymphomas [2]

| PRJNA639892 | ENA

MTORC1/2 Inhibition as a Therapeutic Strategy for PIK3CA Mutant Cancers.

Project description:PIK3CA mutations are common in clinical molecular profiling, yet an effective means to target these cancers has yet to be developed. MTORC1 inhibitors are often used off-label for patients with PIK3CA mutant cancers with only limited data to support this approach. Here we describe a cohort of patients treated with cancers possessing mutations activating the PI3K signaling cascade with minimal benefit to treatment with the MTORC1 inhibitor everolimus. Previously, we demonstrated that dual PI3K/mTOR inhibition could decrease proliferation, induce differentiation, and result in a treatment response in APC and PIK3CA mutant colorectal cancer. However, reactivation of AKT was identified, indicating that the majority of the benefit may be secondary to MTORC1/2 inhibition. TAK-228, an MTORC1/2 inhibitor, was compared with dual PI3K/mTOR inhibition using BEZ235 in murine colorectal cancer spheroids. A reduction in spheroid size was observed with TAK-228 and BEZ235 (-13% and -14%, respectively) compared with an increase of >200% in control (P < 0.001). These spheroids were resistant to MTORC1 inhibition. In transgenic mice possessing Pik3ca and Apc mutations, BEZ235 and TAK-228 resulted in a median reduction in colon tumor size of 19% and 20%, respectively, with control tumors having a median increase of 18% (P = 0.02 and 0.004, respectively). This response correlated with a decrease in the phosphorylation of 4EBP1 and RPS6. MTORC1/2 inhibition is sufficient to overcome resistance to everolimus and induce a treatment response in PIK3CA mutant colorectal cancers and deserves investigation in clinical trials and in future combination regimens.

| S-EPMC6363831 | biostudies-literature

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

Project description:This SuperSeries is composed of the SubSeries listed below.

2020-07-02 | GSE138388 | GEO

HDAC4 reduction: a novel therapeutic strategy to target cytoplasmic huntingtin and ameliorate neurodegeneration

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2014-10-10 | E-GEOD-38237 | biostudies-arrayexpress

Bromodomain protein inhibition: a novel therapeutic strategy in rheumatic diseases.

Project description:The reading of acetylation marks on histones by bromodomain (BRD) proteins is a key event in transcriptional activation. Small molecule inhibitors targeting bromodomain and extra-terminal (BET) proteins compete for binding to acetylated histones. They have strong anti-inflammatory properties and exhibit encouraging effects in different cell types in vitro and in animal models resembling rheumatic diseases in vivo. Furthermore, recent studies that focus on BRD proteins beyond BET family members are discussed.

| S-EPMC6269638 | biostudies-literature

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