Leukemia cell infiltration causes defective erythropoiesis partially through MIP-1α/CCL3.
Y WangA GaoH ZhaoP LuTao ChengF DongY GongS MaY ZhengH ZhangY ZhangJ XuX ZhuWeiping YuanX ZhangS HaoT ChengPublished in: Leukemia (2016)
Leukemia often results in severe anemia, which may significantly contribute to patient mortality and morbidity. However, the mechanisms underlying defective erythropoiesis in leukemia have not been fully elucidated. In this study, we demonstrated that insufficient erythropoiesis in an immunocompetent acute myeloid leukemia (AML) murine model was due to reduced proliferation of megakaryocyte erythroid progenitors and increased apoptosis of erythroblasts. Colony-forming cell assays indicated that the leukemic bone marrow (BM) plasma inhibited erythroid colony formation, whereas they had no inhibitory effect on other types of colonies. Cytokine array analysis demonstrated that the chemokine CCL3 was elevated in the plasma of AML mice and patients. CCL3 inhibited erythroid differentiation of hematopoietic stem cells, common myeloid progenitors and especially megakaryocytic-erythroid progenitors. Administration of the CCR1 antagonist partially recovered the yield of erythroid colonies in the presence of CCL3 or leukemic BM plasma. Mechanistically, we observed an increase of p38 phosphorylation and subsequent downregulation of GATA1 after CCL3 treatment. Furthermore, knockdown of CCL3 attenuated leukemic progression and alleviated anemia. Therefore, our results demonstrate that elevated CCL3 in the leukemic environment suppresses erythropoiesis via CCR1-p38 activation, suggesting a novel mechanism for the erythroid defects observed in leukemia.
Keyphrases
- acute myeloid leukemia
- liver fibrosis
- bone marrow
- liver injury
- allogeneic hematopoietic stem cell transplantation
- drug induced
- stem cells
- signaling pathway
- single cell
- cell therapy
- oxidative stress
- chronic kidney disease
- dendritic cells
- ejection fraction
- regulatory t cells
- type diabetes
- cell death
- metabolic syndrome
- transcription factor
- cell proliferation
- mesenchymal stem cells
- mass spectrometry
- immune response
- cardiovascular events
- newly diagnosed
- endoplasmic reticulum stress
- coronary artery disease
- insulin resistance
- adipose tissue
- protein kinase
- skeletal muscle
- replacement therapy