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Heterogeneous effects of M‐ CSF isoforms on the progression of MLL ‐ AF 9 leukemia
Author(s) -
Wang Rong,
Feng Wenli,
Yang Feifei,
Yang Xiao,
Wang Lina,
Chen Chong,
Hu Yuting,
Ren Qian,
Zheng Guoguang
Publication year - 2018
Publication title -
immunology and cell biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.999
H-Index - 104
eISSN - 1440-1711
pISSN - 0818-9641
DOI - 10.1111/imcb.1029
Subject(s) - myeloid leukemia , leukemia , haematopoiesis , phagocytosis , cancer research , myeloid , granulocyte macrophage colony stimulating factor , gene isoform , immunology , biology , macrophage colony stimulating factor , hematopoietic growth factor , colony stimulating factor , chemistry , macrophage , cytokine , microbiology and biotechnology , stem cell , gene , in vitro , biochemistry
Macrophage colony‐stimulating factor (M‐ CSF ) regulates both malignant cells and microenvironmental cells. Its splicing isoforms show functional heterogeneity. However, their roles on leukemia have not been well established. Here, the expression of total M‐ CSF in patients with hematopoietic malignancies was analyzed. The roles of M‐ CSF isoforms on the progression of acute myeloid leukemia ( AML ) were studied by establishing MLL ‐ AF 9‐induced mouse AML models with high level membrane‐bound M‐ CSF ( mM ‐ CSF ) or soluble M‐ CSF ( sM ‐ CSF ). Total M‐ CSF was highly expressed in myeloid leukemia patients. Furthermore, mM ‐ CSF but not sM ‐ CSF prolonged the survival of leukemia mice. While sM ‐ CSF was more potent to promote proliferation and self‐renew, mM ‐ CSF was more potent to promote differentiation. Moreover, isoforms had different effects on leukemia‐associated macrophages ( LAM s) though they both increase monocytes/macrophages by growth‐promoting and recruitment effects. In addition, mM ‐ CSF promoted specific phagocytosis of leukemia cells by LAM s. RNA ‐seq analysis revealed that mM ‐ CSF enhanced phagocytosis‐associated genes and activated oxidative phosphorylation and metabolism pathway. These results highlight heterogeneous effects of M‐ CSF isoforms on AML progression and the mechanisms of mM ‐ CSF , that is, intrinsically promoting AML cell differentiation and extrinsically enhancing infiltration of macrophages and phagocytosis by macrophages, which may provide potential clues for clinical diagnosis and therapy.