SENP3 Promotes Mantle Cell Lymphoma Development through Regulating Wnt10a Expression

Objective SUMO-specific protease 3(SENP3),a member of the SUMO-specific protease family,reverses the SUMOylation of SUMO-2/3 conjugates.Dysregulation of SENP3 has been proven to be involved in the development of various tumors.However,its role in mantle cell lymphoma(MCL),a highly aggressive lymphoma,remains unclear.This study was aimed to elucidate the effect of SENP3 in MCL.Methods The expression of SENP3 in MCL cells and tissue samples was detected by RT-qPCR,Western blotting or immunohistochemistry.MCL cells with stable SENP3 knockdown were constructed using short hairpin RNAs.Cell proliferation was assessed by CCK-8 assay,and cell apoptosis was determined by flow cytometry.mRNA sequencing(mRNA-seq)was used to investigate the underlying mechanism of SENP3 knockdown on MCL development.A xenograft nude mouse model was established to evaluate the effect of SENP3 on MCL growth in vivo.Results SENP3 was upregulated in MCL patient samples and cells.Knockdown of SENP3 in MCL cells inhibited cell proliferation and promoted cell apoptosis.Meanwhile,the canonical Wnt signaling pathway and the expression of Wnt10a were suppressed after SENP3 knockdown.Furthermore,the growth of MCL cells in vivo was significantly inhibited after SENP3 knockdown in a xenograft nude mouse model.Conclusion SENP3 participants in the development of MCL and may serve as a therapeutic target for MCL.

Zinc finger and BTB domain-containing protein 46 is essential for survival and proliferation of acute myeloid leukemia cell line but dispensable for normal hematopoiesis

Background:Zinc finger and BTB domain-containing protein 46(Zbtb46)is a transcription factor identified in classical dendritic cells,and maintains dendritic cell quiescence in a steady state.Zbtb46 has been reported to be a negative indicator of acute myeloid leukemia(AML).We found that Zbtb46 was expressed at a relatively higher level in hematopoietic stem and progenitor cells(HSPCs)compared to mature cells,and higher in AML cells compared to normal bone marrow(BM)cells.However,the role of Zbtb46in HSPCs and AML cells remains unclear.Therefore,we sought to elucidate the effect of Zbtb46 in normal hematopoiesis and AML cells.Methods:We generated Zbtb46^fl/fl and Zbtb46^fl/fl Mx1-Cre mice.The deletion of Zbtb46 in Zbtb46^fl/fl Mx1-Cre mice was induced by intraperitoneal injection of double-stranded poly(I).poly(C)(poly(I:C)),and referred as Zbtb46 cKO.After confirming the deletion of Zbtb46,the frequency and numbers of HSPCs and mature blood cells were analyzed by flow cytometry.Serial intraperitoneal injection of 5-fluorouracil was administrated to determine the repopulation ability of HSCs from Zbtb46^fl/fl and Zbtb46 cKO mice.The correlation between Zbtb46 expression and prognosis was analyzed using the data from the Cancer Genome Atlas.To investigate the role of Zbtb46 in AML cells,we knocked down the expression of Zbtb46 in THP-1 cells using lentiviral vectors expressing small hairpin RNAs targeting Zbtb46.Cell proliferation rate was determined by cell count assay.Cell apoptosis and bromodeoxyuridine incorporation were determined by flow cytometry.Results:The percentages and absolute numbers of HSPCs and mature blood cells were comparable in Zbtb46 cKO mice and its Zbtb46^fl/fl littermates(Zbtb46^fl/fl vs.Zbtb46 cKO,HPC:801,310±84,282 vs.907,202±97,403,t=0.82,P=0.46;LSK:86,895±7802 vs.102,210±5025,t=1.65,P=0.17;HSC:19,753±3116 vs.17,608±3508,t=0.46,P=0.67).The repopulation ability of HSCs from Zbtb46^fl/fl Mx1-Cre mice was similar to those from Zbtb46^fl/fl control(P=0.26).Zbtb46 had elevated expression in AML cells compared to total BM cells from normal control.Knockdown of Zbtb46 in THP-1 cells led to a significant increase in cell apoptosis and reduced cell growth and proliferation.Conclusion:Collectively,our data indicate that Zbtb46 is essential for survival and proliferation of AML cells,but dispensable for normal hematopoiesis.