| BackgroundAcute myeloid leukemia(AML)is a hematological disorder originated from malignant proliferation of myeloid hematopoietic stem cells,the incidence rate of which increases with age.While the overall survival rate is improved with the progress of AML treatment,the prognosis of most patients is still poor,up to 70%of patients aged 65 or over eventually died of the disease within 1 year after diagnosis.Moreover,recurrence after chemotherapy remains a major challenge for AML treatment.In recent years,the role of bone marrow microenvironment in the occurrence and progression of AML has attracted more and more attention.Leukemic cells are capable of transfroming normal bone marrow niche into leukemic niche,which is conducive to the malignant proliferation of leukemic progenitor cells,promoting the progression of AML.Venetoclax is a novel inhibitor of B-cell lymphoma-2 protein(Bcl-2).Plenty of preclinical and clinical studies have demonstrated that venetoclax is of great clinical benefits to relapsed/refractory acute myeloid leukemia.However,acquired resistance remains a major obstacle in the curative effect of venetoclax in AML.Therefore,it is of great clinical significance to elucidate the mechanism of venetoclax resistance.Besides,it has been proved that bone marrow microenvironment is one of the cardinal mechanism of acquired venetoclax resistance in AML,but the concrete mechanism remains unclear.Moreover,It is commonly believed that histone deacetylase3(HDAC3)is a key regluatory factor in the occurence and progression of malignant deseases.Specifically blocking HDAC3 can effectively inhibit the growth and progression of tumors,suggesting that HDAC3 acts as a potential target for the treatment.Recent work had showed that HDAC3 in bone marrow microenvironment inhibits proliferation of multiple myeloma by regulating the secretion of IL-6 and exosomes.Another study confirmed that bone marrow microenvionment derived GM-CSF mediated AML resistance to venetoclax by activating JAK/STAT signaling pathway.Thus,HDAC3 may act as an significant target in the bone marrow microenvironment mediated drug resistance.There are no reports of HDAC3 in bone marrow microenvironment mediating venetoclax resistance in AML.Our study elucidates the mechanism of bone marrow microenvironment in inducing venetoclax resistance,indicating that targeting HDAC3 in bone marrow microenvironment contrbutes to overcoming venetoclax resistance in AML.MethodsTranswell co-culture assay was ultilized to analyze the up-regulation of HDAC3 in bone marrow stromal cells(HS-5)after HS-5 co-cultured with AML cells compared to mono-culture.Untilizing Cell Counting Kit-8(CCK-8)assay and Apoptosis Detection Kit to confirm HDAC3 mediates AML sensitivity to venetoclax after HDAC3 overexpression and knockdown in human bone marrow stromal cell line HS-5 in vitro.The expression of GM-CSF were downregulated in HDAC3 knockdown bone marrow stromal cells via Q-PCR.AML derived exosomes were collected and characterized by transmission electron microscopy,dynamic light scattering,Zeta potential and protein markers.ResultsHDAC3 in bone marrow stromal cells(HS-5)was up-regulated after HS-5 co-cultured with AML cells via Transwell co-culture assay.HDAC3 overexpression in HS-5 induced AML cells resistance to venetoclax after AML cells incubated with HDAC3 overexpression HS-5 supernatant,while AML cells were re-sensitized to venetoclax after incubated with HDAC3 knockdown HS-5 supernatant,suggesting that HDAC3 in bone marrow stromal cells mediated AML sensitivity to venetoclax treatment.Q-PCR demonstrated that GM-CSF was enriched after HDAC3 knockdown in HS-5.At last,it was confirmed that AML derived exosomes mediated upregulation of HDAC3 in bone marrow stromal cells.ConclusionOur study demonstrated that HDAC3 in bone marrow stromal play an essential role in inducing AML resistance to venetoclax,providing a novol therapeutic target for overcoming the protection of bone marrow microenvironment and ameliorating the prognosis of AML patients. |
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