Acute myeloid leukemia(AML) is an aggressive malignant disease defined by abnormal expansion of myeloid blasts. Despite recent advances in understanding AML pathogenesis and identifying their molecular subtypes based ...Acute myeloid leukemia(AML) is an aggressive malignant disease defined by abnormal expansion of myeloid blasts. Despite recent advances in understanding AML pathogenesis and identifying their molecular subtypes based on somatic mutations, AML is still characterized by poor outcomes, with a 5-year survival rate of only 30%-40%, the majority of the patients dying due to AML relapse. Leukemia stem cells(LSC) are considered to be at the root of chemotherapeutic resistance and AML relapse. Although numerous studies have tried to better characterize LSCs in terms of surface and molecular markers, a specific marker of LSC has not been found, and still the most universally accepted phenotypic signature remains the surface antigens CD34+CD38- that is shared with normal hematopoietic stem cells. Animal models provides the means to investigate the factors responsible for leukemic transformation, the intrinsic differences between secondary post-myeloproliferative neoplasm AML and de novo AML, especially the signaling pathways involved in inflammation and hematopoiesis. However, AML proved to be one of the hematological malignancies that is difficult to engraft even in the most immunodeficient mice strains, and numerous ongoing attempts are focused to develop "humanized mice" that can support the engraftment of LSC. This present review is aiming to in-troduce the field of AML pathogenesis and the concept of LSC, to present the current knowledge on leukemic blasts surface markers and recent attempts to develop best AML animal models.展开更多
On the basis of the newly developed regression diagnostic analysis, the diagnostic method with the assessment of the outliers of the logistic regression model was set up and it was used to analyze the prognosis of the...On the basis of the newly developed regression diagnostic analysis, the diagnostic method with the assessment of the outliers of the logistic regression model was set up and it was used to analyze the prognosis of the patients with acute lymphatic leukemia.展开更多
A significant complication in allogeneic stem cell transplantation is graft versus host disease (GVHD). The use of multipotential mesenchymal stem cells (MMSC) for the amelioration of GVHD has shown promise as a thera...A significant complication in allogeneic stem cell transplantation is graft versus host disease (GVHD). The use of multipotential mesenchymal stem cells (MMSC) for the amelioration of GVHD has shown promise as a therapeutic intervention. Given that MMSC can suppress allogeneic immune responses, there is a concern that using these cells may promote leukemic relapse. We describe a murine model of GVHD in the presence of leukemic cells (L1210). Acute GVHD was induced in DBA mice by transplanting bone marrow and spleen cells from C57Bl/6J mice with or without prior injection of L1210 cells. The recipient mice were monitored for signs of GVHD. The mice were then treated with primary MMSC or a C57Bl bone marrow derived cloned mesenchymal cell line (OMA-AD). The results without L1210 cells, demonstrated that mice treated with primary MMSC that had developed moderate GVHD had increased long-term survival when compared to controls. The group treated with OMA-AD cells showed minimal GVHD so cloned OMA-AD MMSC cells provided a significant protective effect against GVHD, and the survival rate was superior to that of animals treated with primary MMSC on the same day. In the presence of L1210, the control mice all died by day 11, and the mice receiving OMA-AD and L1210 cells died by day 9. Both had minimal GVHD. Only the mice receiving primary MMSC that developed moderate to severe GVHD survived long term. It appears that although MMSC and OMA-AD cells can ameliorate GVHD;the greater immunosuppressive effect of OMA-AD cells permitted the re-growth of the leukemic cells. In contrast, the moderate GVHD that remained after primary MMSC treatment eliminated the leukemia in the majority of mice. These studies demonstrated that in the mouse model, as in man, administration of primary or cloned MMSC ameliorated GVHD. However, complete suppression of GVHD permitted leukemic relapse.展开更多
Summary： Patients with FLT3-ITD^mmutt/NPM1- cytogenetically normal acute myeloid leukemia （CN-AML）, as high-risk molecular group in CN-AML, are associated with a worse prognosis than other CN-AML patients. It is be...Summary： Patients with FLT3-ITD^mmutt/NPM1- cytogenetically normal acute myeloid leukemia （CN-AML）, as high-risk molecular group in CN-AML, are associated with a worse prognosis than other CN-AML patients. It is beneficial to generate xenotransplantation model of FLT3-ITD^mut/NPM1- CN-AML to better understand the pathogenesis and therapeutic strategies of such AML subtype. The purpose of present study was to establish the xenotransplantation model in NOD/SCID mice with FLT3-ITD^mut/NPM1- CN-AML primary cells. The FLT3-ITD^mut/NPM1- CN-AML primary cells from 3 of 7 cases were successfully transplanted into NOD/SCID mice, and human CD45 positive cells were detected in the peripheral blood, spleen and bone marrow of mice by using flow cytometry. Infiltration of human leukemia cells in various organs of mice was observed by using immunohistochemistry. Gene analysis confirmed sustained FLT3/ITD mutation without NPM1 mutation in mice. By performing serial transplantation, it was found that characteristics of the leukemia cells in secondary and tertiary genera- tion models remained unchanged. Moreover, in vivo cytarabine administration could extend survival of NOD/SCID mice, which was consistent with clinical observation. In conclusion, we successfully estab- lished xenotransplantation model of human FLT3-ITD^mut/NPM1- CN-AML in NOD/SCID mice. The model was able to present primary disease and suitable to evaluate the curative effects of new drugs or therapy strategies.展开更多
基金Supported by The project Competitiveness Operational Programme(COP)A1.1.4.,No.P_37_798,Contract 149/26.10.2016(My SMIS2014+:106774)
文摘Acute myeloid leukemia(AML) is an aggressive malignant disease defined by abnormal expansion of myeloid blasts. Despite recent advances in understanding AML pathogenesis and identifying their molecular subtypes based on somatic mutations, AML is still characterized by poor outcomes, with a 5-year survival rate of only 30%-40%, the majority of the patients dying due to AML relapse. Leukemia stem cells(LSC) are considered to be at the root of chemotherapeutic resistance and AML relapse. Although numerous studies have tried to better characterize LSCs in terms of surface and molecular markers, a specific marker of LSC has not been found, and still the most universally accepted phenotypic signature remains the surface antigens CD34+CD38- that is shared with normal hematopoietic stem cells. Animal models provides the means to investigate the factors responsible for leukemic transformation, the intrinsic differences between secondary post-myeloproliferative neoplasm AML and de novo AML, especially the signaling pathways involved in inflammation and hematopoiesis. However, AML proved to be one of the hematological malignancies that is difficult to engraft even in the most immunodeficient mice strains, and numerous ongoing attempts are focused to develop "humanized mice" that can support the engraftment of LSC. This present review is aiming to in-troduce the field of AML pathogenesis and the concept of LSC, to present the current knowledge on leukemic blasts surface markers and recent attempts to develop best AML animal models.
文摘On the basis of the newly developed regression diagnostic analysis, the diagnostic method with the assessment of the outliers of the logistic regression model was set up and it was used to analyze the prognosis of the patients with acute lymphatic leukemia.
文摘A significant complication in allogeneic stem cell transplantation is graft versus host disease (GVHD). The use of multipotential mesenchymal stem cells (MMSC) for the amelioration of GVHD has shown promise as a therapeutic intervention. Given that MMSC can suppress allogeneic immune responses, there is a concern that using these cells may promote leukemic relapse. We describe a murine model of GVHD in the presence of leukemic cells (L1210). Acute GVHD was induced in DBA mice by transplanting bone marrow and spleen cells from C57Bl/6J mice with or without prior injection of L1210 cells. The recipient mice were monitored for signs of GVHD. The mice were then treated with primary MMSC or a C57Bl bone marrow derived cloned mesenchymal cell line (OMA-AD). The results without L1210 cells, demonstrated that mice treated with primary MMSC that had developed moderate GVHD had increased long-term survival when compared to controls. The group treated with OMA-AD cells showed minimal GVHD so cloned OMA-AD MMSC cells provided a significant protective effect against GVHD, and the survival rate was superior to that of animals treated with primary MMSC on the same day. In the presence of L1210, the control mice all died by day 11, and the mice receiving OMA-AD and L1210 cells died by day 9. Both had minimal GVHD. Only the mice receiving primary MMSC that developed moderate to severe GVHD survived long term. It appears that although MMSC and OMA-AD cells can ameliorate GVHD;the greater immunosuppressive effect of OMA-AD cells permitted the re-growth of the leukemic cells. In contrast, the moderate GVHD that remained after primary MMSC treatment eliminated the leukemia in the majority of mice. These studies demonstrated that in the mouse model, as in man, administration of primary or cloned MMSC ameliorated GVHD. However, complete suppression of GVHD permitted leukemic relapse.
基金supported by the National Natural Science Foundation of China (No. 81200380)
文摘Summary： Patients with FLT3-ITD^mmutt/NPM1- cytogenetically normal acute myeloid leukemia （CN-AML）, as high-risk molecular group in CN-AML, are associated with a worse prognosis than other CN-AML patients. It is beneficial to generate xenotransplantation model of FLT3-ITD^mut/NPM1- CN-AML to better understand the pathogenesis and therapeutic strategies of such AML subtype. The purpose of present study was to establish the xenotransplantation model in NOD/SCID mice with FLT3-ITD^mut/NPM1- CN-AML primary cells. The FLT3-ITD^mut/NPM1- CN-AML primary cells from 3 of 7 cases were successfully transplanted into NOD/SCID mice, and human CD45 positive cells were detected in the peripheral blood, spleen and bone marrow of mice by using flow cytometry. Infiltration of human leukemia cells in various organs of mice was observed by using immunohistochemistry. Gene analysis confirmed sustained FLT3/ITD mutation without NPM1 mutation in mice. By performing serial transplantation, it was found that characteristics of the leukemia cells in secondary and tertiary genera- tion models remained unchanged. Moreover, in vivo cytarabine administration could extend survival of NOD/SCID mice, which was consistent with clinical observation. In conclusion, we successfully estab- lished xenotransplantation model of human FLT3-ITD^mut/NPM1- CN-AML in NOD/SCID mice. The model was able to present primary disease and suitable to evaluate the curative effects of new drugs or therapy strategies.
