scholarly journals MSTN mutant promoted bovine muscle satellite cell proliferation by regulating the binding of SMAD2/SMAD3 with CDKN1C

2021 ◽  
Author(s):  
Li Gao ◽  
Miao-Miao Yang ◽  
Ming-Juan Gu ◽  
Yun-Peng Liu ◽  
Cai-Hong Bu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Chromatin Immunoprecipitation ◽  
Muscle Development ◽  
Chip Assay ◽  
Rna Seq ◽  
Wild Type ◽  
Muscle Satellite Cell ◽  
Bovine Muscle ◽  
Expression Of Genes

Abstract Background: Myostatin (MSTN), also known as growth/differentiation factor 8, mostly expressed in skeletal muscle and plays negative roles in regulation of muscle development. Previous studies had proved that MSTN have important effect on cell proliferation. Therefore we aimed to investigate the mechanism of MSTN in regulating the proliferation of bovine muscle satellite cells (MSCs).Methods: Bovine MSCs of MSTN mutant (MT) and wild type (WT) were obtained, we detected the cell proliferation and cell cycle by EdU proliferation assay and Flow cytometry. Then we detected the expression of genes associated with cell cycle by Real-time PCR and Western blotting . RNA-seq and Chromatin immunoprecipitation (ChIP)assay were performed to research the mechanism of MSTN in regulating the cell proliferation. Results: In this study, we found that MSTN mutant promoted the proliferation of MSCs. The expression of CyclinA, CyclinD and CyclinE were all increased after MSTN mutant, while the expression of CDKN1C (P57), CDKN2A, CDKN2C and CDKN2D were down-regulated, which were consistent with the promotion of cell proliferation. Among these genes, CDKN1C(P57) down-regulated most significantly. RNA-seq results showed that MSTN mutant affected the SMAD binding, so we performed ChIP-qPCR and demonstrated that the SMAD2/SMAD3 transcription factor combined with the promoter of CDKN1C thus to increase the expression of CDKN1C, this demonstrating that MSTN regulated the expression of CDKN1C through SMAD2/SMAD3 complex. Finally, overexpression of SMAD3 in wild type cells increased the expression of CDKN1C, further suggested that SMAD3 regulated the expression of CDKN1C. Conclusion: MSTN mutant down-regulated the expression of SMAD2/SMAD3, then reduced the promotion of SMAD2/SMAD3 to the expression of CDKN1C, thus to inhibit the expression of CDKN1C, then promoting the cell cycle.

scholarly journals AXIN2 reduces the survival of porcine induced pluripotent stem cells (piPSCs)

2021 ◽  
Author(s):  
rui zhang ◽  
Shuai Yu ◽  
Qiaoyan Shen ◽  
Wenxu Zhao ◽  
Juqing Zhang ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Cell Proliferation ◽  
Pluripotent Stem Cells ◽  
Culture Medium ◽  
Wnt Signaling Pathway ◽  
Rna Seq ◽  
Expression Of Genes ◽  
Induced Pluripotent ◽  
Effect Of Inhibitors

Abstract BackgroundThe establishment of porcine pluripotent stem cells (piPSCs) is still a critical topic and challenging issue. However, all piPSCs are extremely sensitive to changes of the culture conditions.In addition, the side effect of inhibitors in culture medium confine the pluripotency and practicability. This study aimed to investigate the roles of AXIN in piPSCs and further explore the mechanism. Here, porcine AXIN1 gene and AXIN2 were knockdown, cloned, and overexpressed in piPSCs. Digital RNA-seq was performed to explore the mechanism of cell proliferation and anti-apoptosis. ResultsHere, we found (1): overexpression of the porcine AXIN2 gene significantly reduce the survivability of piPSCs, meanwhile wreck the pluripotency of piPSCs; (2): The Digital RNA-seq analysis reveals that AXIN2, as a negative effector of the WNT signaling pathway, whom after knockdown enhances the expression of genes involved in cell cycle such as CCND1, and reduced the expression of genes related to cell differentiation, cell death, and cell apoptosis. ConclusionAXIN2 could reduce the pluripotency and survival of piPSCs and also provided a potential to simplify the cultrue medium.

The Role of Retinoblastoma Protein in Cell Cycle Regulation: An Updated Review

2021 ◽  
Vol 20 ◽  
Author(s):  
Rabih Roufayel ◽  
Rabih Mezher ◽  
Kenneth B. Storey
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Transcription Factors ◽  
Cell Cycle Control ◽  
Expression Of Genes ◽  
E2f Transcription Factor ◽  
Cellular Energetics ◽  
Development And Differentiation ◽  
E2f Transcription Factors ◽  
Rb Phosphorylation

: Selected transcription factors have critical roles to play in organism survival by regulating the expression of genes that control the adaptations needed to handle stress conditions. The retinoblastoma (Rb) protein coupled with the E2F transcription factor family was demonstrated to have roles in controlling the cell cycle during freezing and associated environmental stresses (anoxia, dehydration). Rb phosphorylation or acetylation at different sites provide a mechanism for repressing cell proliferation that is under the control of E2F transcription factors in animals facing stresses that disrupt cellular energetics or cell volume controls. Other central regulators of the cell cycle including Cyclins, Cyclin dependent kinases (Cdks), and checkpoint proteins detect DNA damage or any improper replication, blocking further progression of cell cycle and interrupting cell proliferation. This review provides an insight into the molecular regulatory mechanisms of cell cycle control, focusing on Rb-E2F along with Cyclin-Cdk complexes typically involved in development and differentiation that need to be regulated in order to survive extreme cellular stress.

scholarly journals BRD4 PROTAC degrader ARV-825 inhibits T-cell acute lymphoblastic leukemia by targeting 'Undruggable' Myc-pathway genes

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Shuiyan Wu ◽  
You Jiang ◽  
Yi Hong ◽  
Xinran Chu ◽  
Zimu Zhang ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Acute Lymphoblastic Leukemia ◽  
Caspase 3 ◽  
Lymphoblastic Leukemia ◽  
Rna Seq ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Bet Protein

Abstract Background T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive disease with a high risk of induction failure and poor outcomes, with relapse due to drug resistance. Recent studies show that bromodomains and extra-terminal (BET) protein inhibitors are promising anti-cancer agents. ARV-825, comprising a BET inhibitor conjugated with cereblon ligand, was recently developed to attenuate the growth of multiple tumors in vitro and in vivo. However, the functional and molecular mechanisms of ARV-825 in T-ALL remain unclear. This study aimed to investigate the therapeutic efficacy and potential mechanism of ARV-825 in T-ALL. Methods Expression of the BRD4 were determined in pediatric T-ALL samples and differential gene expression after ARV-825 treatment was explored by RNA-seq and quantitative reverse transcription-polymerase chain reaction. T-ALL cell viability was measured by CCK8 assay after ARV-825 administration. Cell cycle was analyzed by propidium iodide (PI) staining and apoptosis was assessed by Annexin V/PI staining. BRD4, BRD3 and BRD2 proteins were detected by western blot in cells treated with ARV-825. The effect of ARV-825 on T-ALL cells was analyzed in vivo. The functional and molecular pathways involved in ARV-825 treatment of T-ALL were verified by western blot and chromatin immunoprecipitation (ChIP). Results BRD4 expression was higher in pediatric T-ALL samples compared with T-cells from healthy donors. High BRD4 expression indicated a poor outcome. ARV-825 suppressed cell proliferation in vitro by arresting the cell cycle and inducing apoptosis, with elevated poly-ADP ribose polymerase and cleaved caspase 3. BRD4, BRD3, and BRD2 were degraded in line with reduced cereblon expression in T-ALL cells. ARV-825 had a lower IC50 in T-ALL cells compared with JQ1, dBET1 and OTX015. ARV-825 perturbed the H3K27Ac-Myc pathway and reduced c-Myc protein levels in T-ALL cells according to RNA-seq and ChIP. In the T-ALL xenograft model, ARV-825 significantly reduced tumor growth and led to the dysregulation of Ki67 and cleaved caspase 3. Moreover, ARV-825 inhibited cell proliferation by depleting BET and c-Myc proteins in vitro and in vivo. Conclusions BRD4 indicates a poor prognosis in T-ALL. The BRD4 degrader ARV-825 can effectively suppress the proliferation and promote apoptosis of T-ALL cells via BET protein depletion and c-Myc inhibition, thus providing a new strategy for the treatment of T-ALL.

scholarly journals Loss of MCU prevents mitochondrial fusion in G1-S phase and blocks cell cycle progression and proliferation

2019 ◽  
Vol 12 (579) ◽  
pp. eaav1439 ◽  
Author(s):  
Olha M. Koval ◽  
Emily K. Nguyen ◽  
Velarchana Santhana ◽  
Trevor P. Fidler ◽  
Sara C. Sebag ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Cell Cycle Progression ◽  
Mitochondrial Fission ◽  
Mitochondrial Fusion ◽  
Cycle Phase ◽  
Wild Type ◽  
Mitochondrial Fragmentation ◽  
Cycle Progression ◽  
Regulatory Circuit

The role of the mitochondrial Ca2+uniporter (MCU) in physiologic cell proliferation remains to be defined. Here, we demonstrated that the MCU was required to match mitochondrial function to metabolic demands during the cell cycle. During the G1-S transition (the cycle phase with the highest mitochondrial ATP output), mitochondrial fusion, oxygen consumption, and Ca2+uptake increased in wild-type cells but not in cells lacking MCU. In proliferating wild-type control cells, the addition of the growth factors promoted the activation of the Ca2+/calmodulin-dependent kinase II (CaMKII) and the phosphorylation of the mitochondrial fission factor Drp1 at Ser616. The lack of the MCU was associated with baseline activation of CaMKII, mitochondrial fragmentation due to increased Drp1 phosphorylation, and impaired mitochondrial respiration and glycolysis. The mitochondrial fission/fusion ratio and proliferation in MCU-deficient cells recovered after MCU restoration or inhibition of mitochondrial fragmentation or of CaMKII in the cytosol. Our data highlight a key function for the MCU in mitochondrial adaptation to the metabolic demands during cell cycle progression. Cytosolic CaMKII and the MCU participate in a regulatory circuit, whereby mitochondrial Ca2+uptake affects cell proliferation through Drp1.

YakA, a protein kinase required for the transition from growth to development in Dictyostelium

Development ◽  
1998 ◽  
Vol 125 (12) ◽  
pp. 2291-2302 ◽  
Author(s):  
G.M. Souza ◽  
S. Lu ◽  
A. Kuspa
Keyword(s):  
Cell Cycle ◽  
Protein Kinase ◽  
Basic Protein ◽  
Mrna Levels ◽  
Wild Type ◽  
E Coli ◽  
Cycle Arrest ◽  
Expression Of Genes ◽  
Extracellular Signal ◽  
Nutrient Rich Medium

When Dictyostelium cells starve they arrest their growth and induce the expression of genes necessary for development. We have identified and characterized a protein kinase, YakA, that is essential for the proper regulation of both events. Amino acid sequence and functional similarities indicate that YakA is a homolog of Yak1p, a growth-regulating protein kinase in S. cerevisiae. Purified YakA expressed in E. coli is able to phosphorylate myelin basic protein. YakA-null cells are smaller and their cell cycle is accelerated relative to wild-type cells. When starved, YakA-null cells fail to decrease the expression of the growth-stage gene cprD, and do not induce the expression of genes required for the earliest stages of development. YakA mRNA levels increase during exponential growth and reach a maximum at the point of starvation, consistent with a role in mediating starvation responses. YakA mRNA also accumulates when cells are grown in medium conditioned by cells grown to high density, suggesting that yakA expression is under the control of an extracellular signal that accumulates during growth. Expression of yakA from a conditional promoter causes cell-cycle arrest in nutrient-rich medium and promotes developmental events, such as the expression of genes required for cAMP signaling. YakA appears to regulate the transition from growth to development in Dictyostelium.

scholarly journals A Dominant-Negative PPARγMutant Promotes Cell Cycle Progression and Cell Growth in Vascular Smooth Muscle Cells

PPAR Research ◽  
2009 ◽  
Vol 2009 ◽  
pp. 1-10 ◽  
Author(s):  
Joey Z. Liu ◽  
Christopher J. Lyon ◽  
Willa A. Hsueh ◽  
Ronald E. Law
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Cell Cycle Progression ◽  
Muscle Cells ◽  
Dominant Negative ◽  
Wild Type ◽  
Cycle Progression ◽  
Positive Regulators

PPARγligands have been shown to have antiproliferative effects on many cell types. We herein report that a synthetic dominant-negative (DN) PPARγmutant functions like a growth factor to promote cell cycle progression and cell proliferation in human coronary artery smooth muscle cells (CASMCs). In quiescent CASMCs, adenovirus-expressed DN-PPARγpromoted G1→S cell cycle progression, enhanced BrdU incorporation, and increased cell proliferation. DN-PPARγexpression also markedly enhanced positive regulators of the cell cycle, increasing Rb and CDC2 phosphorylation and the expression of cyclin A, B1, D1, and MCM7. Conversely, overexpression of wild-type (WT) or constitutively-active (CA) PPARγinhibited cell cycle progression and the activity and expression of positive regulators of the cell cycle. DN-PPARγexpression, however, did not up-regulate positive cell cycle regulators in PPARγ-deficient cells, strongly suggesting that DN-PPARγeffects on cell cycle result from blocking the function of endogenous wild-type PPARγ. DN-PPARγexpression enhanced phosphorylation of ERK MAPKs. Furthermore, the ERK specific-inhibitor PD98059 blocked DN-PPARγ-induced phosphorylation of Rb and expression of cyclin A and MCM7. Our data thus suggest that DN-PPARγpromotes cell cycle progression and cell growth in CASMCs by modulating fundamental cell cycle regulatory proteins and MAPK mitogenic signaling pathways in vascular smooth muscle cells (VSMCs).

CBFβ-SMMHC Inhibits G1 to S Progression in Primary Murine and Human Myeloid Progenitors Dependent upon Its AML1-Interaction and Assembly Competence Domains.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1971-1971
Author(s):  
Jenice D’Costa ◽  
Shamik Chaudhuri ◽  
Curt I. Civin ◽  
Alan D. Friedman
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Cell Lines ◽  
Cell Cycle Progression ◽  
Myeloid Cell ◽  
Cyclin D3 ◽  
Wild Type ◽  
Hematopoietic Stem ◽  
Human Cd34 ◽  
Myeloid Progenitors

Abstract CBFβ-SMMHC, encoded by the inv(16) or t(16;16) translocations in approximately 8% of acute myeloid leukemia (AML) cases, is a fusion protein containing amino acids 1-165 of the 182 residue core binding factor β (CBFβ) and the rod domain of smooth muscle myosin heavy chain (SMMHC). The CBFβ domain of CBFβ-SMMHC retains the ability to interact with AML1/RUNX1. The SMMHC domain both mediates multimerization and interacts directly with corepressors, including mSin3A. CBFβ-SMMHC inhibits the expression of AML1-regulated genes, by sequestering AML1 in multimeric complexes and by directly repressing AML1-regulated genes. CBFβ-SMMHC was previously found to slow G1 to S cell cycle progression in hematopoietic cell lines, reflecting repression of AML1-regulated genes required for cell cycle, including cyclin D3. This effect was overcome be exogenous c-Myc or cdk4. In this study, murine marrow or human CD34+ cells were transduced with retroviral or lentiviral vectors, respectively, expressing CBFβ-SMMHC or two mutant variants. CBFβ-SMMHC reduced murine or human myeloid cell proliferation 3- to 4-fold in liquid culture, during a period when control murine cells accumulated 5-fold and human cells 20-fold. CBFβ-SMMHC decreased the formation of myeloid, but not erythroid, colonies 2- to 4-fold, and myeloid colonies expressing CBFβ-SMMHC were markedly reduced in size. Lack of effect on erythroid colonies reflects their lack of expression of AML1. The mutant variant CBFβ-SMMHC(Δ2-11) does not bind AML1 due to a deletion near its N-terminus, and CBFβ-SMMHC(ΔACD) does not multimerize or efficiently bind corepressors due to a 28 residue deletion near its C-terminus. Neither of these mutants, which were expressed at levels similar to wild-type, slowed proliferation or reduced myeloid colonies. CBFβ-SMMHC increased the G1/S ratio in wild-type murine and human progenitors. Proliferation was still slowed in p15(−/−) murine marrow cells transduced with CBFβ-SMMHC, suggesting that additional mutations, such as activation of growth factor receptors and consequent c-myc induction, are required in primary AMLs to allow enhanced proliferation. AML1-ER(T), which contains full-length AML1 and accelerates G1 to S progression in cell lines when activated by 4HT, had an effect opposite to CBFβ-SMMHC, stimulating proliferation of murine or human myeloid progenitors 2-fold. In summary, CBFβ-SMMHC inhibits the proliferation of myeloid progenitors dependent upon inhibition of AML1 and integrity of its Assembly Competence Domain. Targeting the CBFβ-SMMHC ACD or its CBFβ domain may uncover novel therapeutics useful for AML cases expressing this oncoprotein. Furthermore, these findings support a model we have proposed previously which states that mutations which accelerate G1 are required during leukemogenesis by CBFβ-SMMHC and other CBF oncoproteins. Finally, our results lend support to the conclusion that AML1 participates in the regulation of normal myeloid stem-progenitor cell proliferation. Exogenous AML1 may therefore be useful for expansion of hematopoietic stem-progenitor cells.

Excessive Hematopoietic Stem Cell Proliferation Leads to Chromosomal Instability

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4772-4772
Author(s):  
Liliana Souza ◽  
Natalyn Hawk ◽  
Sweta Sengupta ◽  
Carlos Cabrera ◽  
Morgan L. McLemore
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Cell Proliferation ◽  
Stem Cell ◽  
Chromosomal Instability ◽  
Wild Type ◽  
Dna Breaks ◽  
Hematopoietic Stem ◽  
Stem Cell Proliferation ◽  
Double Stranded Dna

Abstract Truncation mutations in the granulocyte colony stimulating factor receptor (G-CSFR), common in severe congenital neutropenia (SCN), lead to excessive stem cell proliferation in response to G-CSF. These G-CSFR mutants are (at least indirectly) implicated in the progression of these patients to acute leukemia. Since SCN patients require continuous G-CSF treatment throughout their lifespan, we hypothesize that excessive stem cell proliferation can lead to DNA damage. Stem cells are relatively quiescent and rarely enter the cell cycle under normal conditions. During the cell cycle cells generate approximately 5000 single strand DNA lesions per nucleus (Vilenchik and Knudson, 2003). Approximately 1% of these lesions are ultimately converted to double strand DNA breaks (DSBs). Hematopoietic stem cells are found within the Sca+ ckit+ Lin- (KLS) population. Wild type and mice bearing a mutant G-CSFR similar to that found in patients with SCN were treated with G-CSF. After 21 days of treatment with G-CSF (10 ug/kg/day), the KLS population in the bone marrow increased four-fold in wild type mice and eight-fold in mutant mice. We isolated Lin-Sca+ bone marrow cells from these G-CSF treated mice and evaluated for the presence of double stranded DNA breaks by staining with anti-phospho-H2AX by immunofluorescence. H2AX is a histone whose phosphorylated form localizes to the site of double stranded DNA breaks. The results showed that there is an 8-fold increase in the DSB in wild type Lin-Sca+ and 10-fold in mutant Lin-Sca+ when compared to cells from untreated mice. This data suggests that excessive proliferation can contribute to an increase in DSBs in hematopoietic stem cells. Investigation of potential mechanisms contributing to DSB formation are ongoing. Understanding the causes and trends of chromosomal instability would improve our understanding of leukemogenesis and potentially reveal novel treatment strategies.

TET2 Downregulation Promotes AML Cell Proliferation Via Pim-1 Expression

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5085-5085
Author(s):  
Qingxiao Chen ◽  
Jingsong He ◽  
Xing Guo ◽  
Jing Chen ◽  
Xuanru Lin ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Flow Cytometry ◽  
Cell Proliferation ◽  
Western Blot ◽  
Cell Lines ◽  
Target Genes ◽  
Leukemia Cell ◽  
Leukemic Cells ◽  
Rna Seq ◽  
Knock Down

Abstract Background: Acute myeloid leukemia (AML) is the most common form of acute leukemia in adults which is still incurable although novel drugs and new combination of chemotherapies are used . With the development of genetic and molecular biology technologies, more and more genes are found to be related to leukemogenesis and drug resistance of AML. TET2, a member of the ten-eleven-translocation gene family which can modify DNA by catalyzing the conversion of 5-mehtyl-cytosine to 5-hydroxymethyl-cytosine , is often inactivated through mutation or deletion in myeloid malignancies. Recent research reported that TET2 knock-down can promote proliferation of hematopoietic stem cells and leukemic cells. Also, several clinical studies showed that patients with TET2 mutation or low levels of TET2 expression have more aggressive disease courses than those with normal levels of TET2. However, the mechanism of the phenomenon is unknown. Our aim is to uncover how TET2 protein level is negatively correlated with AML cell proliferation and to provide a better view of target therapy in AML. Methods: We determined the expression levels of TET2 and other target genes in acute leukemia cell lines, bone marrow AML specimens, and peripheral blood mononuclear cells from healthy donors by qRT-PCR and Western blot. We also determined the mutation status of TET2 in AML cell lines. CCK8 and flow cytometry were used to determine cell proliferation, cell apoptosis, and cell cycle profile. Methylation-specific PCR were used to examine the methylation status in gene promoter regions. Also, we developed TET2 knock-down lentivirus to transfect AML cell lines to examine the effect of TET2 depletion. Last, RNA-seq was used to compare gene expression level changes between TET2 knock-down cell lines and the control cell lines. Results: AML cells from AML cell lines (KG-1,U937, Kasumi, HL-60, THP-1, and MV4-11) and AML patients' specimens expressed lower levels of TET2 than those of PBMC from the healthy donor (P<0.05). Among AML cell lines, U937 barely expressed TET2, while KG-1 expressed TET2 at a relatively higher level than those of other AML cell lines. We constructed a TET2 shRNA to transfect KG-1,THP-1,MV-4-11,Kasumi,and HL-60, and used qRT-PCR and western blot to verify the knock-down efficiency. CCK8 confirmed that knocking down TET2 could increase leukemia cell proliferation (P<0.05). Flow cytometry showed that cell cycle profile was altered in TET2 knock-down cells compared to the negative control cells. In order to identify target genes, we performed RNA-seq on wildtype and TET2 knockdown KG-1 cells and found that the expression of cell cycle related genes, DNA replication related genes, and some oncogenes were changed. We focused on Pim-1, an oncogene related to leukemogenesis, which was significantly up-regulated in the RNA-seq profile. Western blot and qPCR verified the RNA-seq results of Pim-1 expression in the transfected cells . Also, AML patients' bone marrow samples (n=35) were tested by qPCR and 28 of them were found to express low TET2 but high Pim-1 with the other 7 being opposite. For detailed exploration in expression regulation of Pim-1 via TET2, we screened genes affecting Pim-1 expression and found SHP-1, a tumor suppress gene which is often silenced by promoter methylation in AML. Western blot band of SHP-1 was attenuated in TET2 knockdown KG-1 cells. Moreover, methylation-specific PCR showed that after knocking down TET2 in KG-1 cell line, the promoter regions were methylated much more than the control cells. These results indicated that the function of TET2 in epigenetic modulation plays an important role in regulating Pim-1 expression. Finally, using flow cytometry and CCK8 we surprisingly found that knocking down TET2 expression could lead leukemic cells (KG-1, THP-1 and MV-4-11) more sensitive to Pim-1 inhibitor (SGI-1776 free base) and decitabine (a demethylation agent treating MDS and AML) (P<0.05). Conclusion: Our study showed that knocking down TET2 promoted leukemic cell proliferation. This phenomenon may correlate to Pim-1 up-regulation. Our clinical data also showed that the expression of TET2 and Pim-1 have an inverse relationship. The mechanism of TET2 regulating Pim-1 expression may be related to the epigenetic modulation function of TET2. Finally, we found TET2 downregulation could increase leukemia vulnerability to Pim-1 inhibitor and decitbine, and provide a novel view of target therapy in AML. Disclosures No relevant conflicts of interest to declare.

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