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A unique role of p53 haploinsufficiency or loss in the development of acute myeloid leukemia with FLT3-ITD mutation.

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机构： [1]Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany. [2]National Research Center for Translational Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. [3]Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, and Department of Hematology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China. [4]Institute of Pathology, Hannover Medical School, Hannover, Germany. [5]Department of Human Genetics, Hannover Medical School, Hannover, Germany. [6]Institute for Laboratory Animal Science and Central Animal Facility, Hannover Medical School, Hannover, Germany. [7]Research Core Unit Genomics, Hannover Medical School, Hannover, Germany. [8]Department of Hematology, Oncology, Clinical Immunology, University of Tübingen, Tübingen, Germany. [9]Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. [10]University Children's Hospital, Department of General Pediatrics and Pediatric Hematology and Oncology, Tübingen, Germany. [11]AML Diagnostic Laboratory, Department of Pediatric Hematology-Oncology, University of Duisburg-Essen, Essen, Germany. [12]Department of Hematology, Shanghai Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. [13]Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany. li.zhixiong@mh-hannover.de.

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With an incidence of ~50%, the absence or reduced protein level of p53 is much more common than TP53 mutations in acute myeloid leukemia (AML). AML with FLT3-ITD (internal tandem duplication) mutations has an unfavorable prognosis and is highly associated with wt-p53 dysfunction. While TP53 mutation in the presence of FLT3-ITD does not induce AML in mice, it is not clear whether p53 haploinsufficiency or loss cooperates with FLT3-ITD in the induction of AML. Here, we generated FLT3-ITD knock-in; p53 knockout (heterozygous and homozygous) double-transgenic mice and found that both alterations strongly cooperated in the induction of cytogenetically normal AML without increasing the self-renewal potential. At the molecular level, we found the strong upregulation of Htra3 and the downregulation of Lin28a, leading to enhanced proliferation and the inhibition of apoptosis and differentiation. The co-occurrence of Htra3 overexpression and Lin28a knockdown, in the presence of FLT3-ITD, induced AML with similar morphology as leukemic cells from double-transgenic mice. These leukemic cells were highly sensitive to the proteasome inhibitor carfilzomib. Carfilzomib strongly enhanced the activity of targeting AXL (upstream of FLT3) against murine and human leukemic cells. Our results unravel a unique role of p53 haploinsufficiency or loss in the development of FLT3-ITD + AML.© 2021. The Author(s).

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出版当年[2020]版：

大类 | 1 区

医学

小类 | 1 区血液学 2 区肿瘤学

最新[2025]版：

大类 | 1 区

医学

小类 | 1 区血液学 2 区肿瘤学

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第一作者机构： [1]Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.

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