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Epigenetic drugs selectively target a population of AML cells which are positive for CD123 cell surface markers and are chemoresistant

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

ORGANISM(S): Homo sapiens

PROVIDER: GSE114649 | GEO | 2020/08/28

REPOSITORIES: GEO

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Epigenetic drugs selectively target a population of AML cells which are positive for CD123 cell surface markers and are chemoresistant II

Project description:Gene expression profiling was performed on OCI-AML2 R50 drug resistant leukemia cell line before or after Romidepsin treatment.

2020-08-28 | GSE114648 | GEO

Epigenetic drugs selectively target a population of AML cells which are positive for CD123 cell surface markers and are chemoresistant I

Project description:Global gene expression profiling was performed on OCI-AML2 leukemia cell line, R3 and R50 drug resistant cell lines.

2020-08-28 | GSE108142 | GEO

Epigenetic drugs selectively target a population of AML cells which are positive for CD123 cell surface markers and are chemoresistant

Project description:Epigenetic drugs selectively target a population of AML cells which are positive for CD123 cell surface markers and are chemoresistant

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Epigenetic drugs selectively target a population of AML cells which are positive for CD123 cell surface markers and are chemoresistant II

Project description:Epigenetic drugs selectively target a population of AML cells which are positive for CD123 cell surface markers and are chemoresistant II

| PRJNA472053 | ENA

Epigenetic drugs selectively target a population of AML cells which are positive for CD123 cell surface markers and are chemoresistant I

Project description:Epigenetic drugs selectively target a population of AML cells which are positive for CD123 cell surface markers and are chemoresistant I

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Drugs That Mimic Hypoxia Selectively Target EBV-Positive Gastric Cancer Cells.

Project description:Latent infection of Epstein-Barr virus (EBV) is associated with lymphoid and epithelial cell cancers, including 10% of gastric carcinomas. We previously reported that hypoxia inducible factor-1α (HIF-1α) induces EBV's latent-to-lytic switch and identified several HIF-1α-stabilizing drugs that induce this viral reactivation. Here, we tested three classes of these drugs for preferential killing of the EBV-positive gastric cancer AGS-Akata cell line compared to its matched EBV-negative AGS control. We observed preferential killing with iron chelators [Deferoxamine (DFO); Deferasirox (DFX)] and a prolyl hydroxylase inhibitor (BAY 85-3934 (Molidustat)), but not with a neddylation inhibitor [MLN4924 (Pevonedistat)]. DFO and DFX also induced preferential killing of the EBV-positive gastric cancer AGS-BDneo and SNU-719 cell lines. Preferential killing was enhanced when low-dose DFX (10 μM) was combined with the antiviral prodrug ganciclovir. DFO and DFX induced lytic EBV reactivation in approximately 10% of SNU-719 and 20-30% of AGS-Akata and AGS-BDneo cells. However, neither DFO nor DFX significantly induced synthesis of lytic EBV proteins in xenografts grown in NSG mice from AGS-Akata cells above the level observed in control-treated mice. Therefore, these FDA-approved iron chelators are less effective than gemcitabine at promoting EBV reactivation in vivo despite their high specificity and efficiency in vitro.

| S-EPMC10046841 | biostudies-literature

Ibrutinib selectively targets FLT3-ITD in mutant FLT3-positive AML.

Project description: Not available

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Evaluation of switch-mediated costimulation in trans on universal CAR-T cells (UniCAR) targeting CD123-positive AML.

Project description:Chimeric antigen receptor T cells (CAR-T) targeting CD19 have achieved significant success in patients with B cell malignancies. To date, implementation of CAR-T in other indications remains challenging due to the lack of truly tumor-specific antigens as well as control of CAR-T activity in patients. CD123 is highly expressed in acute myeloid leukemia (AML) blasts including leukemia-initiating cells making it an attractive immunotherapeutic target. However, CD123 expression in normal hematopoietic progenitor cells and endothelia bears the risk of severe toxicities and may limit CAR-T applications lacking fine-tuned control mechanisms. Therefore, we recently developed a rapidly switchable universal CAR-T platform (UniCAR), in which CAR-T activity depends on the presence of a soluble adapter called targeting module (TM), and confirmed clinical proof-of-concept for targeting CD123 in AML with improved safety. As costimulation via 4-1BB ligand (4-1BBL) can enhance CAR-T expansion, persistence, and effector functions, a novel CD123-specific TM variant (TM123-4-1BBL) comprising trimeric single-chain 4-1BBL was developed for transient costimulation of UniCAR-T cells (UniCAR-T) at the leukemic site in trans. TM123-4-1BBL-directed UniCAR-T efficiently eradicated CD123-positive AML cells in vitro and in a CDX in vivo model. Moreover, additional costimulation via TM123-4-1BBL enabled enhanced expansion and persistence with a modulated UniCAR-T phenotype. In addition, the increased hydrodynamic volume of TM123-4-1BBL prolonged terminal plasma half-life and ensured a high total drug exposure in vivo. In conclusion, expanding the soluble adapter optionality for CD123-directed UniCAR-T maintains the platforms high anti-leukemic efficacy and immediate control mechanism for a flexible, safe, and individualized CAR-T therapy of AML patients.

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CD123 Is Consistently Expressed on NPM1-Mutated AML Cells.

Project description:NPM1-mutated (NPM1mut) acute myeloid leukemia (AML) comprises about 30% of newly diagnosed AML in adults. Despite notable advances in the treatment of this frequent AML subtype, about 50% of NPM1mut AML patients treated with conventional treatment die due to disease progression. CD123 has been identified as potential target for immunotherapy in AML, and several anti-CD123 therapeutic approaches have been developed for AML resistant to conventional therapies. As this antigen has been previously reported to be expressed by NPM1mut cells, we performed a deep flow cytometry analysis of CD123 expression in a large cohort of NPM1mut and wild-type samples, examining the whole blastic population, as well as CD34+CD38- leukemic cells. We demonstrate that CD123 is highly expressed on NPM1mut cells, with particularly high expression levels showed by CD34+CD38- leukemic cells. Additionally, CD123 expression was further enhanced by FLT3 mutations, which frequently co-occur with NPM1 mutations. Our results identify NPM1-mutated and particularly NPM1/FLT3 double-mutated AML as disease subsets that may benefit from anti-CD123 targeted therapies.

| S-EPMC7865228 | biostudies-literature

CD123 and More: How to Target the Cell Surface of Blastic Plasmacytoid Dendritic Cell Neoplasm.

Project description:Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive leukemia derived from plasmacytoid dendritic cells (pDCs). It is associated with a remarkably poor prognosis and unmet need for better therapies. Recently, the first-in-class CD123-targeting therapy, tagraxofusp, was approved for treatment of BPDCN. Other CD123-targeting strategies are in development, including bispecific antibodies and combination approaches with tagraxofusp and other novel agents. In other blood cancers, adoptive T-cell therapy using chimeric antigen receptor (CAR)-modified T cells represents a promising new avenue in immunotherapy, showing durable remissions in some relapsed hematologic malignancies. Here, we report on novel and innovative therapies in development to target surface molecules in BPDCN currently in clinical trials or in preclinical stages. We also discuss new cell surface targets that may have implications for future BPDCN treatment.

| S-EPMC9099711 | biostudies-literature

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