Bone marrow endothelial cell-derived interleukin-4 contributes to thrombocytopenia in acute myeloid leukemia
Ai Gao,
Yuemin Gong,
Caiying Zhu,
Wanzhu Yang,
Qing Li,
Mei Zhao,
Shihui Ma,
Jianyong Li,
Sha Hao,
Hui Cheng,
Tao Cheng
Affiliations
Ai Gao
State Key Laboratory of Experimental Hematology;Institute of Hematology and Blood Disease Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin
Yuemin Gong
State Key Laboratory of Experimental Hematology;Institute of Hematology and Blood Disease Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin;Department of Hematology, the First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Jiangsu
Caiying Zhu
State Key Laboratory of Experimental Hematology;Institute of Hematology and Blood Disease Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin
Wanzhu Yang
State Key Laboratory of Experimental Hematology;Institute of Hematology and Blood Disease Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin
Qing Li
State Key Laboratory of Experimental Hematology;Institute of Hematology and Blood Disease Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin
Mei Zhao
State Key Laboratory of Experimental Hematology;Institute of Hematology and Blood Disease Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin
Shihui Ma
State Key Laboratory of Experimental Hematology;Institute of Hematology and Blood Disease Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin
Jianyong Li
Department of Hematology, the First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Jiangsu
Sha Hao
State Key Laboratory of Experimental Hematology;Institute of Hematology and Blood Disease Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin;Center for Stem Cell Medicine, Chinese Academy of Medical Sciences, Tianjin;Department of Stem Cell & Regenerative Medicine, Peking Union Medical College, Tianjin, China
Hui Cheng
State Key Laboratory of Experimental Hematology;Institute of Hematology and Blood Disease Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin;Center for Stem Cell Medicine, Chinese Academy of Medical Sciences, Tianjin;Department of Stem Cell & Regenerative Medicine, Peking Union Medical College, Tianjin, China
Tao Cheng
State Key Laboratory of Experimental Hematology;Institute of Hematology and Blood Disease Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin;Center for Stem Cell Medicine, Chinese Academy of Medical Sciences, Tianjin;Department of Stem Cell & Regenerative Medicine, Peking Union Medical College, Tianjin, China
Normal hematopoiesis can be disrupted by the leukemic bone marrow microenvironment, which leads to cytopenia-associated symptoms including anemia, hemorrhage and infection. Thrombocytopenia is a major and sometimes fatal complication in patients with acute leukemia. However, the mechanisms underlying defective thrombopoiesis in leukemia have not been fully elucidated. In the steady state, platelets are continuously produced by megakaryocytes. Using an MLL-AF9-induced acute myeloid leukemia mouse model, we demonstrated a preserved number and proportion of megakaryocyte-primed hematopoietic stem cell subsets, but weakened megakaryocytic differentiation via both canonical and non-canonical routes. This primarily accounted for the dramatic reduction of megakaryocytic progenitors observed in acute myeloid leukemia bone marrow and a severe disruption of the maturation of megakaryocytes. Additionally, we discovered overproduction of interleukin-4 from bone marrow endothelial cells in acute myeloid leukemia and observed inhibitory effects of interleukin-4 throughout the process of megakaryopoiesis in vivo. Furthermore, we observed that inhibition of interleukin-4 in combination with induction chemotherapy not only promoted recovery of platelet counts, but also prolonged the duration of remission in our acute myeloid leukemia mouse model. Our study elucidates a new link between interleukin-4 signaling and defective megakaryopoiesis in acute myeloid leukemia bone marrow, thereby offering a potential therapeutic target in acute myeloid leukemia.