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Haematologica 2019 Volume 10410):1950-1961
Hematopoiesis
Bone marrow endothelial cell-derived interleukin-4 contributes to thrombocytopenia in acute myeloid leukemia
Ai Gao,1,2,# Yuemin Gong,1,2,3,# Caiying Zhu,1,2 Wanzhu Yang,1,2 Qing Li,1,2
Mei Zhao,1,2 Shihui Ma,1,2 Jianyong Li,3 Sha Hao,1,2,4,5,* Hui Cheng1,2,4,5,* and Tao Cheng1,2,4,5,*
1State Key Laboratory of Experimental Hematology; 2Institute of Hematology and Blood Disease Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin; 3Department of Hematology, the First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Jiangsu; 4Center for Stem Cell Medicine, Chinese Academy of Medical Sciences, Tianjin and 5Department of Stem Cell & Regenerative Medicine, Peking Union Medical College, Tianjin, China
ABSTRACT
Normal hematopoiesis can be disrupted by the leukemic bone mar- row 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 prima- rily accounted for the dramatic reduction of megakaryocytic progenitors observed in acute myeloid leukemia bone marrow and a severe disrup- tion 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 sig- naling and defective megakaryopoiesis in acute myeloid leukemia bone marrow, thereby offering a potential therapeutic target in acute myeloid leukemia.
Introduction
Historical data have revealed that the majority of patients with leukemia die of cytopenia-associated complications including infection and hemorrhage.1,2 Progressive suppression of normal hematopoiesis is the major cause of cytopenias in leukemias and other malignancies.3 Normal hematopoiesis is more seriously compromised than leukemic hematopoiesis in acute myeloid leukemia (AML), even with a low leukemia cell burden.4 Maintenance of normal hematopoietic homeostasis depends on the bone marrow (BM) microenvironment, which is the site where hematopoietic stem cells (HSC) reside and are regulated through inter- cellular contacts and signaling molecules.5 Interactions between leukemic cells and the BM microenvironment are attracting intense attention. Studies have shown that leukemia causes significant changes in a variety of cells and cytokines in the BM microenvironment, which impair the function of supporting normal
#These authors contributed equally to this work.
Correspondence:
SHA HAO
haosha@ihcams.ac.cn
HUI CHENG
chenghui@ihcams.ac.cn
TAO CHENG
chengtao@ihcams.ac.cn
Received: December 14, 2018. Accepted: February 20, 2019. Pre-published: February 21, 2019.
doi:10.3324/haematol.2018.214593
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haematologica | 2019; 104(10)
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