Evidence map›Paper›PMID 38475919›Full record

ArticleJournal of experimental & clinical cancer research : CR2024

C/EBPα-p30 confers AML cell susceptibility to the terminal unfolded protein response and resistance to Venetoclax by activating DDIT3 transcription.

Mengbao Du, Mowang Wang, Meng Liu, Shan Fu, Yu Lin, Yankun Huo, Jian Yu, Xiaohong Yu, Chong Wang, Haowen Xiao and 1 more

Open access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Journal of experimental & clinical cancer research : CR, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.

0numbers the graph read from it
0cells of the map it votes in
4citing papers in PubMed
2.3field-weighted citation impact, top 13% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

4 citing papers in PubMed, 5 citations in OpenAlex.

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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

11 authors at 3 institutions in 2 countries.

Mengbao Du *Bone Marrow Transplantation Center of The First Affiliated Hospital & Liangzhu Laboratory, Zhejiang University School of Medicine, No.79 Qingchun Rd., Hangzhou, 310003, Zhejiang Province, People's Republic of China.
Mowang Wang *Bone Marrow Transplantation Center of The First Affiliated Hospital & Liangzhu Laboratory, Zhejiang University School of Medicine, No.79 Qingchun Rd., Hangzhou, 310003, Zhejiang Province, People's Republic of China.
Meng Liu *Department of Hematological Malignancies Translational Science, Gehr Family Center for Leukemia Research, Hematologic Malignancies and Stem Cell Transplantation Institute, Beckman Research Institute, City of Hope Medical Center, Duarte, CA, USA.
Shan FuBone Marrow Transplantation Center of The First Affiliated Hospital & Liangzhu Laboratory, Zhejiang University School of Medicine, No.79 Qingchun Rd., Hangzhou, 310003, Zhejiang Province, People's Republic of China.
Yu LinBone Marrow Transplantation Center of The First Affiliated Hospital & Liangzhu Laboratory, Zhejiang University School of Medicine, No.79 Qingchun Rd., Hangzhou, 310003, Zhejiang Province, People's Republic of China.
Yankun HuoHematology Department, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe Dong Rd., Zhengzhou, 450000, Henan Province, People's Republic of China.
Jian YuBone Marrow Transplantation Center of The First Affiliated Hospital & Liangzhu Laboratory, Zhejiang University School of Medicine, No.79 Qingchun Rd., Hangzhou, 310003, Zhejiang Province, People's Republic of China.
Xiaohong YuInstitute of Hematology, Zhejiang University, Hangzhou, China.
Chong WangHematology Department, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe Dong Rd., Zhengzhou, 450000, Henan Province, People's Republic of China. fccwangc@zzu.edu.cn.
Haowen XiaoDepartment of Hematology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China. haowenxiaoxiao@zju.edu.cn.
Limengmeng WangBone Marrow Transplantation Center of The First Affiliated Hospital & Liangzhu Laboratory, Zhejiang University School of Medicine, No.79 Qingchun Rd., Hangzhou, 310003, Zhejiang Province, People's Republic of China. wanglmmzx@zju.edu.cn.
Zhejiang University · CNFirst Affiliated Hospital of Zhengzhou University · CNCity of Hope · US

Funding

Henan Province Health and Wellness Science and Technology Innovation Leader Project YXKC2021011Henan Provincial Medical Science and Technology Tackle Plan Project SBGJ202302041Huadong Medicine Joint Funds of the Zhejiang Provincial Natural Science Foundation of China under Grant No. LHDMZ23H160001National Natural Science Foundation of China 82170141National Natural Science Foundation of China 82270221
6 · The paper itself

Abstract

backgroundAcute myeloid leukemia (AML) with biallelic (CEBPA

methodsHuman AML cell lines and murine myeloid precursor cell line 32Dcl3 cells were infected with recombinant lentiviruses to knock down CEBPA expression or over-express the two isoforms of C/EBPα. Quantitative real-time PCR and western immunoblotting were employed to determine gene expression levels. Cell apoptosis rates were assessed by flow cytometry. CFU assays were utilized to evaluate the differentiation potential of 32Dcl3 cells. Luciferase reporter analysis, ChIP-seq and ChIP-qPCR were used to validate the transcriptional regulatory ability and affinity of each C/EBPα isoform to specific sites at DDIT3 promoter. Finally, an AML xenograft model was generated to evaluate the in vivo therapeutic effect of agents.

resultsWe found a negative correlation between CEBPA expression and DDIT3 levels in AML cells. After knockdown of CEBPA, DDIT3 expression was upregulated, resulting in increased apoptotic rate of AML cells induced by ER stress. Cebpa knockdown in mouse 32Dcl3 cells also led to impaired cell viability due to upregulation of Ddit3, thereby preventing leukemogenesis since their differentiation was blocked. Then we discovered that the two isoforms of C/EBPα regulate DDIT3 transcription in the opposite way. C/EBPα-p30 upregulated DDIT3 transcription when C/EBPα-p42 downregulated it instead. Both isoforms directly bound to the promoter region of DDIT3. However, C/EBPα-p30 has a unique binding site with stronger affinity than C/EBPα-p42. These findings indicated that balance of two isoforms of C/EBPα maintains protein homeostasis and surveil leukemia, and at least partially explained why AML cells with disrupted C/EBPα-p42 and/or overexpressed C/EBPα-p30 exhibit better response to chemotherapy stress. Additionally, we found that a low C/EBPα p42/p30 ratio induces resistance in AML cells to the BCL2 inhibitor venetoclax since BCL2 is a major target of DDIT3. This resistance can be overcome by combining ER stress inducers, such as tunicamycin and sorafenib in vitro and in vivo.

conclusionOur results indicate that AML patients with a low C/EBPα p42/p30 ratio (e.g., CEBPA

Indexed as

Antineoplastic AgentsBridged Bicyclo Compounds, HeterocyclicLeukemia, Myeloid, AcuteSulfonamidesAnimalsCCAAT-Enhancer-Binding Protein-alphaCCAAT-Enhancer-Binding ProteinsHumansMiceProtein IsoformsProto-Oncogene Proteins c-bcl-2Transcription Factor CHOPUnfolded Protein ResponseAntineoplastic AgentsBridged Bicyclo Compounds, HeterocyclicCCAAT-Enhancer-Binding Protein-alphaCCAAT-Enhancer-Binding ProteinsCEBPA protein, humanCEBPA protein, mouseDDIT3 protein, humanDdit3 protein, mouseProtein IsoformsProto-Oncogene Proteins c-bcl-2SulfonamidesTranscription Factor CHOPvenetoclaxAcute myeloid leukemiaCCAAT-enhancer-binding protein αCEBPA mutationDNA damage-inducible transcript 3Endoplasmic reticulum stressUnfolded protein responseVenetoclax resistance

Identifiers

PMID38475919
PMCPMC10936103
OpenAlexW4392752435

What OpenQuestion holds

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LicenceCC BY
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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.