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Backgroud Compelling research suggests that a population of cancer stem cells(CSCs)is able to regenerate or self-renew resulting in therapeutic resistance and disease progression: this is particularly true in chronic myeloid leukemia(CML).Methods We have previously isolated fetal liver kinase-1-positive(Flk1+)cells carrying the BCR/ABL fusion gene from the bone marrow of Philadelphia chromosome-positive(Ph+)patients with hemangioblast property.We examined their biological characteristics as well as immunological function and further detected the possible molecular mechenism involoved in the leukemia genesis.Results We showed that CML patient-derived Flk1+CD31-CD34-MSCs had normal morphology,phenotype and karyotype but appeared impaired immuno-modulatory function.The capacity of Flk1+CD31-CD34-MSCs from CML patients to inhibit T lymphocyte activation and proliferation was impaired in vitro.CML patients-derived MSCs have dampening immuno-modulatory functions,suggesting that the dysregulation of hematopoiesis and immune response might originate from MSCs rather than HSCs.These Ph+ putative CML hemangioblast upregulated TGF-β1 and resultantly activated matrix metalloproteinase-9(MMP-9)to enhance s-KitL and s-ICAM-1 secretion,which activated c-kit+ HSCs from the quiescent state to proliferative state.Further studies showed that phosphatidylinositol-3 kinase(PI3K)/Akt/nuclear factor(NF)-κB signaling pathway was involved in CML pathogenesis.Conclusion Flk1+CD31-CD34-MSCs that express BCR/ABL leukemia oncogene are hemangioblasts and they play a critical role in the progression of CML through PI3K/Akt/NF-κ B beyond HSCs.