Ten-eleven translocation 2(TET2)functions as a methylcytosine dioxygenase that catalyzes the iterative oxidation of 5-methylcytosine to 5-hydroxymethylcytosine,5-formylcytosine and 5-carboxylcytosine.TET2 has been sho...Ten-eleven translocation 2(TET2)functions as a methylcytosine dioxygenase that catalyzes the iterative oxidation of 5-methylcytosine to 5-hydroxymethylcytosine,5-formylcytosine and 5-carboxylcytosine.TET2 has been shown to be crucial for the maintenance and differentiation of hematopoietic stem cells,and its deletion and/or mutations results in the expansion of HSPCs,and leads to hematological malignancies.TET2 mutations were found in a variety of hematological disorders such as CMML(60%),MDS(30%),MPN(13%)and AML(20%).Interestingly,it was shown that CMML patients with TET2 mutation exhibited fewer platelets than CMML patients without TET2 mutation.However,the role and function of TET2 in platelet hemostasis and thrombogenesis is not well defined.Here in this study,using a genetically engineered Tet2 deletion mouse model,we found that the absence of Tet2 caused a decrease in the proportion of MEP cells and hyperploid megakaryocytes.Additionally,Tet2-deficient mice displayed impaired platelet activation and aggregation under stimulation of ADP and low concentrations of thrombin,although the modestly compromised platelet function and MEP differentiation in Tet2-deficient mice could be compensated without affecting blood coagulation function.Our study indicate that Tet2 deficiency leads to mild impairment of platelet function and thrombopoiesis in mice.展开更多
Colony-stimulating factor 3 receptor(CSF3R)mutations have been identified in a variety of myeloid disorders.Although CSF3R point mutations(eg,T618I)are emerging as key players in chronic neutrophilic leukemia/atypical...Colony-stimulating factor 3 receptor(CSF3R)mutations have been identified in a variety of myeloid disorders.Although CSF3R point mutations(eg,T618I)are emerging as key players in chronic neutrophilic leukemia/atypical chronic myelogenous leukemia,the significance of rarer CSF3R mutations is unknown.Here,we report a 32-year-old female who was diagnosed as Philadelphia chromosome-positive acute lymphoblastic leukemia(Ph^(+)ALL)with the CSF3R M696T mutation and was undergone unrelated donor hematopoietic stem cell transplantation.The patient achieved complete remission with chemotherapy in combination with tyrosine kinase inhibitor(TKI)and long-term survival by unrelated donor transplantation.Meanwhile,we performed a series of experiments using murine interleukin 3(IL-3)-dependent Ba/F3 cell line to evaluate the transforming capacity of the CSF3R M696T mutation.We confirmed the presence of a CSF3R M696T germline mutation in this patient which was inherited from her mother.The in vitro experiment results showed that the CSF3R M696T mutation contributes marginally to the tumor transformation of Ba/F3 cells,indicating that CSF3R M696T mutation was neutral in tumor transformation ability.We concluded that TKI is effective in patients with the CSF3R M696T mutation in Ph+ALL and donors with CSF3R M696T mutation might still be selected as the candidate for transplantation.展开更多
基金This work was partially supported by the funds from the CAMS Innovation Fund for Medical Sciences(2016-I2M-1-017 and 2017-I2M-3-015)National Natural Science Foundation of China(81629001,81421002,81600136,81770105,81970149).
文摘Ten-eleven translocation 2(TET2)functions as a methylcytosine dioxygenase that catalyzes the iterative oxidation of 5-methylcytosine to 5-hydroxymethylcytosine,5-formylcytosine and 5-carboxylcytosine.TET2 has been shown to be crucial for the maintenance and differentiation of hematopoietic stem cells,and its deletion and/or mutations results in the expansion of HSPCs,and leads to hematological malignancies.TET2 mutations were found in a variety of hematological disorders such as CMML(60%),MDS(30%),MPN(13%)and AML(20%).Interestingly,it was shown that CMML patients with TET2 mutation exhibited fewer platelets than CMML patients without TET2 mutation.However,the role and function of TET2 in platelet hemostasis and thrombogenesis is not well defined.Here in this study,using a genetically engineered Tet2 deletion mouse model,we found that the absence of Tet2 caused a decrease in the proportion of MEP cells and hyperploid megakaryocytes.Additionally,Tet2-deficient mice displayed impaired platelet activation and aggregation under stimulation of ADP and low concentrations of thrombin,although the modestly compromised platelet function and MEP differentiation in Tet2-deficient mice could be compensated without affecting blood coagulation function.Our study indicate that Tet2 deficiency leads to mild impairment of platelet function and thrombopoiesis in mice.
基金This work was supported by funds from the Ministry of Science and Technology of China(2018YFA0107801 and 2017YFA0103402)the National Natural Science Foundation of China(82070192,81770105,81770155,and 81670171).
文摘Colony-stimulating factor 3 receptor(CSF3R)mutations have been identified in a variety of myeloid disorders.Although CSF3R point mutations(eg,T618I)are emerging as key players in chronic neutrophilic leukemia/atypical chronic myelogenous leukemia,the significance of rarer CSF3R mutations is unknown.Here,we report a 32-year-old female who was diagnosed as Philadelphia chromosome-positive acute lymphoblastic leukemia(Ph^(+)ALL)with the CSF3R M696T mutation and was undergone unrelated donor hematopoietic stem cell transplantation.The patient achieved complete remission with chemotherapy in combination with tyrosine kinase inhibitor(TKI)and long-term survival by unrelated donor transplantation.Meanwhile,we performed a series of experiments using murine interleukin 3(IL-3)-dependent Ba/F3 cell line to evaluate the transforming capacity of the CSF3R M696T mutation.We confirmed the presence of a CSF3R M696T germline mutation in this patient which was inherited from her mother.The in vitro experiment results showed that the CSF3R M696T mutation contributes marginally to the tumor transformation of Ba/F3 cells,indicating that CSF3R M696T mutation was neutral in tumor transformation ability.We concluded that TKI is effective in patients with the CSF3R M696T mutation in Ph+ALL and donors with CSF3R M696T mutation might still be selected as the candidate for transplantation.
