Leukemia cell infiltration causes defective erythropoiesis partially through MIP-1α/CCL3.
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.
State Key Laboratory of Experimental Hematology, Institute of Hematology & Blood Diseases Hospital, Tianjin, China.
Y
Y
Wang
State Key Laboratory of Experimental Hematology, Institute of Hematology & Blood Diseases Hospital, Tianjin, China.
A
A
Gao
State Key Laboratory of Experimental Hematology, Institute of Hematology & Blood Diseases Hospital, Tianjin, China.
H
H
Zhao
State Key Laboratory of Experimental Hematology, Institute of Hematology & Blood Diseases Hospital, Tianjin, China.
P
P
Lu
State Key Laboratory of Experimental Hematology, Institute of Hematology & Blood Diseases Hospital, Tianjin, China.|Center for Stem Cell Medicine, Tianjin, China.
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0000-0003-4395-1095
H
Cheng
State Key Laboratory of Experimental Hematology, Institute of Hematology & Blood Diseases Hospital, Tianjin, China.
F
F
Dong
State Key Laboratory of Experimental Hematology, Institute of Hematology & Blood Diseases Hospital, Tianjin, China.
Y
Y
Gong
State Key Laboratory of Experimental Hematology, Institute of Hematology & Blood Diseases Hospital, Tianjin, China.
S
S
Ma
State Key Laboratory of Experimental Hematology, Institute of Hematology & Blood Diseases Hospital, Tianjin, China.
Y
Y
Zheng
State Key Laboratory of Experimental Hematology, Institute of Hematology & Blood Diseases Hospital, Tianjin, China.
H
H
Zhang
State Key Laboratory of Experimental Hematology, Institute of Hematology & Blood Diseases Hospital, Tianjin, China.
Y
Y
Zhang
State Key Laboratory of Experimental Hematology, Institute of Hematology & Blood Diseases Hospital, Tianjin, China.
J
J
Xu
State Key Laboratory of Experimental Hematology, Institute of Hematology & Blood Diseases Hospital, Tianjin, China.|Center for Stem Cell Medicine, Tianjin, China.|Department of Stem Cell and Regenerative Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.
X
X
Zhu
State Key Laboratory of Experimental Hematology, Institute of Hematology & Blood Diseases Hospital, Tianjin, China.|Center for Stem Cell Medicine, Tianjin, China.|Department of Stem Cell and Regenerative Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.
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0000-0001-8288-5022
W
Yuan
State Key Laboratory of Experimental Hematology, Institute of Hematology & Blood Diseases Hospital, Tianjin, China.|Department of Stem Cell and Regenerative Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.|Department of Medicine, Loma Linda University, Loma Linda, CA, USA.
X
X
Zhang
State Key Laboratory of Experimental Hematology, Institute of Hematology & Blood Diseases Hospital, Tianjin, China.|Center for Stem Cell Medicine, Tianjin, China.|Department of Stem Cell and Regenerative Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.
S
S
Hao
State Key Laboratory of Experimental Hematology, Institute of Hematology & Blood Diseases Hospital, Tianjin, China.|Center for Stem Cell Medicine, Tianjin, China.|Department of Stem Cell and Regenerative Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.|Collaborative Innovation Center for Cancer Medicine, Tianjin, China.|Tianjin Key Laboratory of Blood Cell Therapy and Technology, Tianjin, China.
T
T
Cheng
D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation; D054405:Chemokine CCL3 / Q000097:blood / Q000494:pharmacology*; D004195:Disease Models, Animal; D018450:Disease Progression; D004900:Erythroblasts; D004920:Erythropoiesis / Q000187:drug effects; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000473:pathology*; D017254:Leukemic Infiltration / Q000473:pathology*; D008533:Megakaryocytes; D051379:Mice; D010766:Phosphorylation; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D054405:Chemokine CCL3; D048051:p38 Mitogen-Activated Protein Kinases