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1.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 29(5): 1369-1374, 2021 Oct.
Article in Chinese | MEDLINE | ID: mdl-34627412

ABSTRACT

OBJECTIVE: To establish a leukemia mouse model induced by transplantation of hematopoietic cells from mixed lineage leukemia (MLL)-AF9 transgenic mice so as to provide the basis for the mechanism research and drug screening of acute myeloid leukemia (AML). METHODS: MLL-AF9 knock-in mice were bred and identified. When the mice developed leukemia, white blood cell (WBC) count in peripheral blood, flow cytometry and morphology method were analyzed to identify the disease. When the WBC count in peripheral blood was more than 100×109/L, bone marrow cells and spleen cells were collected and cryopresevated. After resuscitation, the cells were injected into 4.5 Gy irradiated wild C57BL/6J mice through the tail vein to develop MLL-AF9 leukemia mouse model. Finally, the therapeutic effect was evaluated by positive drug on the model. RESULTS: The natural onset times of leukemia on MLL-AF9 knock-in mice were 22-28 weeks. The spleens of the transgenic mice enlarged and the bone marrow showed the immature forms of myeloid leukemia cells. Both the bone marrow and spleen cells highly expressed myeloid markers, CD11b and Gr-1. At least 0.5×106 bone marrow cells and 2.5×106 spleen cells could induce leukemia in all recipient mice, and the median survival times of mice were 20 days and 36 days, respectively. Experimental treatment was carried out on the leukemia mouse model transplanted with MLL-AF9 spleen cells, and it was found that the traditional chemotherapy drug cytarabine could delay the onset of leukemia and prolong the survival time of the mouse model. CONCLUSION: The leukemia model of hematopoietic cell transplantation based on MLL-AF9 transgenic mice is successfully established, which can be used for the study of the pathogenesis and evaluation of therapeutic effect of AML.


Subject(s)
Hematopoietic Stem Cell Transplantation , Leukemia, Myeloid, Acute , Animals , Mice , Mice, Inbred C57BL , Mice, Transgenic , Oncogene Proteins, Fusion
2.
Int J Hematol ; 113(2): 254-262, 2021 Feb.
Article in English | MEDLINE | ID: mdl-33074481

ABSTRACT

Differentiation therapies with all-trans retinoic acid (ATRA) have been successful in treating acute promyelocytic leukemia, a rare subtype of acute myeloid leukemia (AML). However, their efficacy is limited in the case of other AML subtypes. Here, we show that the combination of ATRA with salt-inducible kinase (SIK) inhibition significantly enhances ATRA-mediated AML differentiation. SIK inhibition augmented the ability of ATRA to induce growth inhibition and G1 cell cycle arrest of AML cells. Moreover, combining ATRA and SIK inhibition synergistically activated the Akt signaling pathway but not the MAPK pathway. Pharmacological blockade of Akt activity suppressed the combination-induced differentiation, indicating an essential role for Akt in the action of the combination treatment. Taken together, our study reveals a novel role for SIK in the regulation of ATRA-mediated AML differentiation, implicating the combination of ATRA and SIK inhibition as a promising approach for future differentiation therapy.


Subject(s)
Antineoplastic Agents/pharmacology , Cell Differentiation/drug effects , Drug Resistance, Neoplasm/drug effects , Leukemia, Myeloid, Acute/metabolism , Protein Serine-Threonine Kinases/antagonists & inhibitors , Tretinoin/pharmacology , Antineoplastic Agents/therapeutic use , Apoptosis/drug effects , Biomarkers , Cell Cycle/drug effects , Cell Line, Tumor , Humans , Immunohistochemistry , Immunophenotyping , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/pathology , MAP Kinase Signaling System , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Proto-Oncogene Proteins c-akt/metabolism , Tretinoin/therapeutic use
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