Cell stem cell: reveal the new mechanism of maintaining leukemia stem cells! It is expected to strike cancer stem cells completely

April 28, 2019 / bioin / - most chronic myeloid leukemia patients can be treated with tyrosine kinase inhibitors These drugs are very effective, can produce deep remission and prolong survival However, these patients still have resting leukemic stem cells, so they must continue to use inhibitors to maintain remission These "dormant cells" are leukemic stem cells that remain at rest in the microenvironment of the bone marrow Bone marrow is a special anatomical site, which is known to maintain normal hematopoietic stem cells (precursors of all blood cells) However, the role of leukemic stem cells in the maintenance of chronic myeloid leukemia remains unclear Photo source: in a study published in the journal Cell stem cell, Dr Ravi Bhatia of the University of Alabama at Birmingham and his colleagues, together with the University of Zurich and Osaka University's collaborators describe how a specific cytokine specifically expressed in specific bone marrow cells controls the rest of these LTLS The chemokine is CXCL12, and the bone marrow cells expressing chemokine are mesenchymal cells Mesenchymal cells have been known to help maintain normal stem cells "In patients treated with tyrosine kinase inhibitors, long-term dormant leukemia stem cells are the main obstacle in the treatment of chronic myeloid leukemia." Bhatia said "This work identifies specific mesenchymal stromal cells responsible for keeping leukemia stem cells at rest and resistant to treatment, and shows that targeting these interactions can activate leukemia stem cells and make them sensitive to treatment, thereby enhancing their ability to clear cancer cells." Bhatia is a professor of medicine at UAB, head of the Department of Hematology and oncology, and deputy director of the UAB O'Neal comprehensive cancer center CXCL12 is expressed in bone marrow to control the maintenance of hematopoietic stem cells Four kinds of cells in bone marrow are known to produce CXCL12 in large quantities In a mouse experiment, Bhatia and his colleagues caused each cell to produce CXCL12 gene deletions, and then studied how each deletion affected the regulation of leukemic stem cells They found that removing CXCL12 from mesenchymal stromal cells, rather than from the other three types of bone marrow microenvironment cells expressing CXCL12, promoted the development of leukemia and reduced the survival rate of mice These results are related to the cell cycle increase and expansion of chronic myeloid leukemia stem cells However, circulating leukemic stem cells become sensitive to tyrosine kinase therapy, resulting in their elimination increasing Bone marrow imaging studies showed that the recombinant stromal cells Co located with leukemic stem cells in the discrete area of bone marrow When CXCL12 was absent, the co localization regions of MSCs and leukemic stem cells disappeared, which further supported the importance of CXCL12 expression in maintaining leukemic stem cell niche "These results suggest that MSCs expressing CXCL12 act as specific regulatory regions to maintain static, therapeutic resistant leukemic stem cells in the bone marrow," Bhatia said Compared with mesenchymal stromal cells, the absence of CXCL12 expression in bone marrow microenvironment endothelial cells resulted in a decrease in the number of stem cells in chronic myeloid leukemia and prolonged the survival rate of mice This suggests that endothelial cells expressing CXCL12 contribute to the maintenance of leukemic stem cells Therefore, the cells with mesenchymal stromal cells and endothelial cells expressing CXCL12 have different regulatory effects on leukemia stem cells Reference: puneet Agarwal et al, mesenchymal nice specific expression of CXCL12 controls quiet of treatment resistant leukemia stem cells, cell stem cell (2019) Doi: 10.1016/j.stem.2019.02.018