General Information of the Disease (ID: DIS00012)
Name
Diffuse large B-cell lymphoma
ICD
ICD-11: 2A81
Full List of Target(s) of This Ferroptosis-centered Disease
Unspecific Target
In total 2 item(s) under this target
Experiment 1 Reporting the Ferroptosis-centered Disease Response by This Target [1]
Responsed Disease Diffuse large B-cell lymphoma [ICD-11: 2A81]
Responsed Drug Dimethyl fumarate Approved
Responsed Regulator Signal transducer and activator of transcription 3 (STAT3) Suppressor
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model A-431 cells Skin squamous cell carcinoma Homo sapiens CVCL_0037
A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
HaCaT cells Normal Homo sapiens CVCL_0038
HT-1080 cells Fibrosarcoma Homo sapiens CVCL_0317
Huh-7 cells Hepatocellular carcinoma Homo sapiens CVCL_0336
SK-MEL-28 cells Cutaneous melanoma Homo sapiens CVCL_0526
SMMC-7721 cells Endocervical adenocarcinoma Homo sapiens CVCL_0534
HEK-293T cells Normal Homo sapiens CVCL_0063
In Vivo Model
For the VFN-D1 patient-derived and the HBL-1 xenograft mouse models, adult female NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice were implanted subcutaneously with 1 x 107 cells in PBS (300 ul). Once mice developed palpable tumors, the animals were randomized into control, DMF (daily i.p. treatment with 500 ul of 3 mg/ml DMF in PBS), ABT-199 (daily p.o. treatment with 100 mg/kg in ethanol/PhosalG/PEG400) or DMF+ABT-199 treated groups.

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Response regulation Dimethyl fumarate (DMF) induces lipid peroxidation and thus ferroptosis, particularly in GCB diffuse large B-cell lymphoma (DLBCL). In ABC DLBCL cells, which are addicted to NF-kB and STAT3 survival signaling, DMF treatment efficiently inhibits the activity of the IKK complex and Janus kinases .
Experiment 2 Reporting the Ferroptosis-centered Disease Response by This Target [2]
Responsed Disease Diffuse large B-cell lymphoma [ICD-11: 2A81]
Responsed Drug Artesunate Investigative
Responsed Regulator Signal transducer and activator of transcription 3 (STAT3) Suppressor
Pathway Response JAK-STAT signaling pathway hsa04630
Ferroptosis hsa04216
Autophagy hsa04140
Apoptosis hsa04210
Cell Process Cell ferroptosis
Cell apoptosis
Cell autophagy
Cell proliferation
In Vitro Model U-2932 cells Diffuse large B-cell lymphoma Homo sapiens CVCL_1896
SU-DHL-2 cells Diffuse large B-cell lymphoma Homo sapiens CVCL_9550
SU-DHL-4 cells Diffuse large B-cell lymphoma Homo sapiens CVCL_0539
SU-DHL-6 cells Diffuse large B-cell lymphoma Homo sapiens CVCL_2206
HEK-293T cells Normal Homo sapiens CVCL_0063
In Vivo Model
Female NOD/SCID mice (age, 6 weeks; body weight, 20 ± 2 g) were purchased from Beijing Huafukang Biotechnology Co., Ltd., maintained under pathogen-free conditions and allowed free access to sterilized food and water. After a week of adaptation to their surroundings, 1 x 107 U2932 cells were subcutaneously injected into the right flank near the hind leg of each mouse. Following the growth of palpable tumors (tumor volume of 50-100 mm3), the mice were randomly divided into two groups (n = 5 mice/group) and treated with 100 ul normal saline (NS) or ART (120 mg/kg/day) via intraperitoneal injection.

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Response regulation Artesunate (ART) was found to exert its effects via inhibition of STAT3 activation. ART may induce apoptosis and cell cycle arrest to inhibit cell proliferation, and regulate autophagy and ferroptosis via impairing the STAT3 signaling pathway in diffuse large B cell lymphoma (DLBCL) cells.
Transferrin receptor protein 1 (TFRC)
In total 1 item(s) under this target
Experiment 1 Reporting the Ferroptosis-centered Disease Response by This Target [3]
Target for Ferroptosis Marker/Suppressor/Driver
Responsed Disease Diffuse large B-cell lymphoma [ICD-11: 2A81]
Responsed Regulator Histone-lysine N-methyltransferase EZH2 (EZH2) Suppressor
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model Karpas-422 cells Diffuse large B-cell lymphoma Homo sapiens CVCL_1325
U-2932 cells Diffuse large B-cell lymphoma Homo sapiens CVCL_1896
WILL-2 cells Diffuse large B-cell lymphoma Homo sapiens CVCL_1901
HEK-293T cells Normal Homo sapiens CVCL_0063
In Vivo Model
All animal experiments were approved by the Institutional Animal Care and Use Committee of Shanghai Institute of Materia Medica and performed in accordance with the Association for Assessment and Accreditation of Laboratory Animal Care. Tumors were measured twice weekly and volumes were calculated using the formula TV=length x width2 x 1/2.

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Response regulation EZH2 inhibition upregulated-TfR-1 dysregulation leads to drug resistance in EZH2 WT diffuse large B-cell lymphoma (DLBCL). On the other hand, EZH2i impaired the occurrence of ferroptosis by upregulating the heat shock protein family A (Hsp70) member 5 (HSPA5) and stabilizing glutathione peroxidase 4 (GPX4), a ferroptosis suppressor.
Phospholipid hydroperoxide glutathione peroxidase (GPX4)
In total 1 item(s) under this target
Experiment 1 Reporting the Ferroptosis-centered Disease Response by This Target [3]
Target for Ferroptosis Suppressor
Responsed Disease Diffuse large B-cell lymphoma [ICD-11: 2A81]
Responsed Regulator Histone-lysine N-methyltransferase EZH2 (EZH2) Suppressor
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model Karpas-422 cells Diffuse large B-cell lymphoma Homo sapiens CVCL_1325
U-2932 cells Diffuse large B-cell lymphoma Homo sapiens CVCL_1896
WILL-2 cells Diffuse large B-cell lymphoma Homo sapiens CVCL_1901
HEK-293T cells Normal Homo sapiens CVCL_0063
In Vivo Model
All animal experiments were approved by the Institutional Animal Care and Use Committee of Shanghai Institute of Materia Medica and performed in accordance with the Association for Assessment and Accreditation of Laboratory Animal Care. Tumors were measured twice weekly and volumes were calculated using the formula TV=length x width2 x 1/2.

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Response regulation EZH2 inhibition upregulated-TfR-1 dysregulation leads to drug resistance in EZH2 WT diffuse large B-cell lymphoma (DLBCL). On the other hand, EZH2i impaired the occurrence of ferroptosis by upregulating the heat shock protein family A (Hsp70) member 5 (HSPA5) and stabilizing glutathione peroxidase 4 (GPX4), a ferroptosis suppressor.
Cystine/glutamate transporter (SLC7A11)
In total 1 item(s) under this target
Experiment 1 Reporting the Ferroptosis-centered Disease Response by This Target [4]
Target for Ferroptosis Suppressor
Responsed Disease Diffuse large B-cell lymphoma [ICD-11: 2A81]
Responsed Drug Imidazole ketone erastin Investigative
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model SU-DHL-1 cells Anaplastic large cell lymphoma Homo sapiens CVCL_0538
SU-DHL-2 cells Diffuse large B-cell lymphoma Homo sapiens CVCL_9550
SU-DHL-6 cells Diffuse large B-cell lymphoma Homo sapiens CVCL_2206
SU-DHL-8 cells Diffuse large B-cell lymphoma Homo sapiens CVCL_2207
SU-DHL-10 cells Diffuse large B-cell lymphoma Homo sapiens CVCL_1889
SU-DHL-16 cells B-cell non-Hodgkin lymphoma Homo sapiens CVCL_1890
A3/Kawakami cells Diffuse large B-cell lymphoma Homo sapiens CVCL_1062
OCI-LY8 cells Diffuse large B-cell lymphoma Homo sapiens CVCL_8803
U-937 cells Adult acute monocytic leukemia Homo sapiens CVCL_0007
DoHH2 cells Diffuse large B-cell lymphoma Homo sapiens CVCL_1179
HBL-1 cells Non-Hodgkin lymphoma Homo sapiens CVCL_M572
U-2932 cells Diffuse large B-cell lymphoma Homo sapiens CVCL_1896
SU-DHL-7 cells Diffuse large B-cell lymphoma Homo sapiens CVCL_4380
SU-DHL-9 cells Diffuse large B-cell lymphoma Homo sapiens CVCL_4379
A4/Fukuda cells B acute lymphoblastic leukemia Homo sapiens CVCL_1064
WSU-NHL cells Diffuse large B-cell lymphoma Homo sapiens CVCL_1793
SU-DHL-5 cells Diffuse large B-cell lymphoma Homo sapiens CVCL_1735
Karpas-422 cells Diffuse large B-cell lymphoma Homo sapiens CVCL_1325
In Vivo Model
NOD/SCID mice (12-weeks of age and ~28 g weight) were weighed before injection and divided into groups of 3 mice per cage. Mice were dosed using three different routes, IP and PO with 50 mg/kg IKE, and IV with 17 mg/kg IKE. Samples were collected at 0, 1, 3, 4, and 8 h from three mice per time point. Additionally, three mice per group were used as controls by administration with equivalent amount of vehicle 1 by IP, PO, and IV, and samples were collected at 8 h. At the appropriate time, mice were sacrificed by CO2 asphyxiation for 3 min and ~0.5 mL of blood was collected via cardiac puncture.

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Response regulation Imidazole ketone erastin (IKE) is a potent, selective, and metabolically stable system xc- (SLC7A11)inhibitor. In addition, biodegradable polyethylene glycol-poly(lactic-co-glycolic acid) nanoparticles were employed to aid in IKE delivery and exhibited reduced toxicity compared with free IKE in a diffuse large B cell lymphoma (DLBCL) xenograft model.
References
Ref 1 Dimethyl fumarate induces ferroptosis and impairs NF-B/STAT3 signaling in DLBCL. Blood. 2021 Sep 9;138(10):871-884. doi: 10.1182/blood.2020009404.
Ref 2 Artesunate induces apoptosis, autophagy and ferroptosis in diffuse large B cell lymphoma cells by impairing STAT3 signaling. Cell Signal. 2021 Dec;88:110167. doi: 10.1016/j.cellsig.2021.110167. Epub 2021 Oct 7.
Ref 3 Dysregulation of iron homeostasis by TfR-1 renders EZH2 wild type diffuse large B-cell lymphoma resistance to EZH2 inhibition. Acta Pharmacol Sin. 2023 May 25. doi: 10.1038/s41401-023-01097-4. Online ahead of print.
Ref 4 Imidazole Ketone Erastin Induces Ferroptosis and Slows Tumor Growth in a Mouse Lymphoma Model. Cell Chem Biol. 2019 May 16;26(5):623-633.e9. doi: 10.1016/j.chembiol.2019.01.008. Epub 2019 Feb 21.