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Role of non-coding RNAs in classical hodgkin’s lymphoma treated within the EuroNet-PHL-C2 study

ABSTRACT: Pediatric Hodgkin lymphoma (HL) is a highly curable malignancy, yet a significant proportion of patients show inadequate early treatment responses despite intensive chemotherapy. The ability to identify these patients at diagnosis or early during therapy is critical for guiding treatment intensity and improving long‑term outcomes while minimizing unnecessary toxicity. MicroRNAs (miRNAs) have emerged as promising biomarkers in HL due to their stability in blood, ease of detection, and central role in regulating gene expression relevant to tumor biology. This study aims to determine whether specific microRNA (miRNA) expression patterns can serve as predictive and prognostic biomarkers in pediatric Hodgkin lymphoma. It will identify signatures—defined by upregulated oncogenic and/or downregulated tumor‑suppressive miRNAs—associated with inadequate early PET (ERAqPET) responses after two cycles of OEPA chemotherapy. miRNA profiles at diagnosis and during treatment will be compared between ERAqPET‑positive and ERAqPET‑negative patients, and correlated with treatment outcomes to establish a biomarker profile for early risk stratification. The goal is to develop a clinically applicable tool to identify high‑risk patients before or early in therapy, enabling tailored treatment that preserves high cure rates while minimizing long‑term adverse effects.

ORGANISM(S): Homo sapiens

PROVIDER: GSE308257 | GEO | 2026/04/10

REPOSITORIES: GEO

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Project description:Disease relapse and resistance to chemotherapy represent challenging issues in a subset of Hodgkin Lymphoma (HL) patients. Activity and mechanism(s) of action of a novel PI3K/ERK dual inhibitor AEZS-136 (Ãterna Zentaris GmbH, Germany, EU) were examined in L-540, SUP-HD1, KM-H2 and L-428 cell lines. Despite exposure to AEZS-136 induced a significant cell growth inhibition (range, 30-80%), levels of caspase-independent cell death and mitochondrial dysfunction, were only observed in L-540 (62 Â±9 vs 14 Â±3%, P â¤.0001) and SUP-HD1 (46 Â±2% vs 15 Â±2%, P â¤.0001) cells. Gene expression profiling indicated that the effects of AEZS-136 treatment are associated with the modulation of cell cycle and cell death pathways. Exposure to AEZS-136 resulted in sustained production of reactive oxygen species (ROS) and activation of necroptotic cell death. The necroptosis inhibitor Necrostatin-1 prevented AEZS-136-induced ROS production, mitochondrial injury, activation of JNK and cell death. Knockdown experiments identified the immediate early response 3 (IER3) as a key signaling molecule that mediates AEZS-136-resistance to oxidative death of HL cells. Furthermore, in vivo xenograft studies demonstrated a 40-70% reduction in tumor burden (P < 0.0001) and a 10-fold increase in tumor necrosis in AEZS-136-treated animals compared to control mice. These data support further clinical evaluation of AEZS-136 in refractory/relapsed HL. The Hodgkin lymphoma cell lines were obtained from the DSMZ (Braunschweig, Germany, EU). Cells were routinely maintained in RPMI medium 1640 (Lonza, Basel, Switzerland) supplemented with 20% FBS (Lonza) and 2 mM glutamine (Lonza). Cells were maintained at 37Â°C in a water-saturated atmosphere of 5% CO2 in air. 4x106 HL cells were seeded in 75 cm2 flask and, after 24 hrs, cells were treated with 10 ÂµM AEZS-136 (Aeterna Zentaris, Frankfurt, Germany, EU) in culture medium for 24 hours. At the end of treatment, cells were collected and RNA extracted.

Project description:Disease relapse and resistance to chemotherapy represent challenging issues in a subset of Hodgkin Lymphoma (HL) patients. Activity and mechanism(s) of action of a novel PI3K/ERK dual inhibitor AEZS-136 (Ãterna Zentaris GmbH, Germany, EU) were examined in L-540, SUP-HD1, KM-H2 and L-428 cell lines. Despite exposure to AEZS-136 induced a significant cell growth inhibition (range, 30-80%), levels of caspase-independent cell death and mitochondrial dysfunction, were only observed in L-540 (62 Â±9 vs 14 Â±3%, P â¤.0001) and SUP-HD1 (46 Â±2% vs 15 Â±2%, P â¤.0001) cells. Gene expression profiling indicated that the effects of AEZS-136 treatment are associated with the modulation of cell cycle and cell death pathways. Exposure to AEZS-136 resulted in sustained production of reactive oxygen species (ROS) and activation of necroptotic cell death. The necroptosis inhibitor Necrostatin-1 prevented AEZS-136-induced ROS production, mitochondrial injury, activation of JNK and cell death. Knockdown experiments identified the immediate early response 3 (IER3) as a key signaling molecule that mediates AEZS-136-resistance to oxidative death of HL cells. Furthermore, in vivo xenograft studies demonstrated a 40-70% reduction in tumor burden (P < 0.0001) and a 10-fold increase in tumor necrosis in AEZS-136-treated animals compared to control mice. These data support further clinical evaluation of AEZS-136 in refractory/relapsed HL. The Hodgkin lymphoma cell lines were obtained from the DSMZ (Braunschweig, Germany, EU). Cells were routinely maintained in RPMI medium 1640 (Lonza, Basel, Switzerland) supplemented with 20% FBS (Lonza) and 2 mM glutamine (Lonza). Cells were maintained at 37Â°C in a water-saturated atmosphere of 5% CO2 in air. 4x106 HL cells were seeded in 75 cm2 flask and, after 24 hrs, cells were treated with 10 ÂµM AEZS-136 (Aeterna Zentaris, Frankfurt, Germany, EU) in culture medium for 2 hours. At the end of treatment, cells were collected and RNA extracted.

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Role of non-coding RNAs in classical hodgkin’s lymphoma treated within the EuroNet-PHL-C2 study

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