Sox13 and M2-like leukemia-associated macrophages contribute to endogenous IL-34 caused accelerated progression of acute myeloid leukemia

• Published in: Cell death & disease Vol. 14; no. 5; pp. 308 - 10
• Main Authors: Zhang, Dongyue, Cui, Xiaoxi, Li, Yifei, Wang, Rong, Wang, Hao, Dai, Yibo, Ren, Qian, Wang, Lina, Zheng, Guoguang
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 06.05.2023; Springer Nature B.V; Nature Publishing Group
• Subjects: 13/1; 13/100; 13/21; 13/89; 14/63; 38/39; 38/91; 42/109; 631/250/127/1213; 631/67/1990/283/1897; 631/67/327; 631/67/70; 631/67/71; 64/60; 96/31; Acute myeloid leukemia; Animals; Antibodies; Autoantigens; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Culture; Cell Differentiation; Cell proliferation; Colonies; Colony-stimulating factor; DNA microarrays; Gene expression; Humans; Immunology; Infiltration; Interleukins - genetics; Leukemia; Leukemia, Myeloid, Acute - metabolism; Life Sciences; Macrophage Colony-Stimulating Factor; Macrophages - metabolism; Malignancy; Mice; Microenvironments; Monocytes; Phagocytes; Phenotypes; SOXD Transcription Factors; Transplantation; Tumor Microenvironment
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-023-05822-z

Interleukin 34 (IL-34) mainly plays physiologic and pathologic roles through the sophisticated multi-ligand signaling system, macrophage colony-stimulating factor (M-CSF, CSF-1)/IL-34-CSF-1R axis, which exhibits functional redundancy, tissue-restriction and diversity. This axis is vital for the survival, differentiation and function of monocytic lineage cells and plays pathologic roles in a broad range of diseases. However, the role of IL-34 in leukemia has not been established. Here MLL-AF9 induced mouse acute myeloid leukemia (AML) model overexpressing IL-34 (MA9-IL-34) was used to explore its role in AML. MA9-IL-34 mice exhibited accelerated disease progression and short survival time with significant subcutaneous infiltration of AML cells. MA9-IL-34 cells showed increased proliferation. In vitro colony forming assays and limiting dilution transplantation experiments demonstrated that MA9-IL-34 cells had elevated leukemia stem cell (LSC) levels. Gene expression microarray analysis revealed a panel of differential expressed genes including Sex-determining region Y (SRY)-box 13 (Sox13). Furthermore, a positive correlation between the expressions of IL-34 and Sox13 was detected human datasets. Knockdown of Sox13 rescued the enhanced proliferation, high LSC level and subcutaneous infiltration in MA9-IL-34 cells. Moreover, more leukemia-associated macrophages (LAMs) were detected in MA9-IL-34 microenvironment. Additionally, those LAMs showed M2-like phenotype since they expressed high level of M2-associated genes and had attenuated phagocytic potential, suggesting that LAMs should also contribute to IL-34 caused adverse phenotypes. Therefore, our findings uncover the intrinsic and microenvironmental mechanisms of IL-34 in AML and broadens the knowledge of M-CSF/IL-34-CSF-1R axis in malignancies.