Loss of IRF7 accelerates acute myeloid leukemia progression and induces VCAM1-VLA-4 mediated intracerebral invasion

• Published in: Oncogene Vol. 41; no. 16; pp. 2303 - 2314
• Main Authors: Wang, Hao, Zhang, Dongyue, Cui, Xiaoxi, Dai, Yibo, Wang, Chenchen, Feng, Wenli, Lv, Xiaoqian, Li, Yifei, Wang, Lina, Ru, Yongxin, Zhang, Yingchi, Ren, Qian, Zheng, Guoguang
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 15.04.2022; Nature Publishing Group
• Subjects: 13; 14/1; 14/19; 14/35; 38/39; 38/89; 38/91; 42/100; 631/67/1922; 631/67/1990/283/1897; 631/67/70; 631/67/71; 64/110; 64/60; 82/29; 96/31; Acute myeloid leukemia; Animal models; Animals; Apoptosis; Cell adhesion molecules; Cell Biology; Cell proliferation; Central nervous system; Disease Models, Animal; Disease Progression; Homeodomain Proteins - metabolism; Human Genetics; Humans; Inflammation; Integrin alpha4beta1 - metabolism; Interferon; Interferon regulatory factor; Interferon regulatory factor 7; Interferon Regulatory Factor-7 - genetics; Interferon Regulatory Factor-7 - metabolism; Internal Medicine; Leukemia; Leukemia, Myeloid, Acute - pathology; Medicine; Medicine & Public Health; Mice; Microenvironments; Oncology; Repressor Proteins - metabolism; Stem cells; Tumor Microenvironment - genetics; Vascular cell adhesion molecule 1; Vascular Cell Adhesion Molecule-1 - genetics; Vascular Cell Adhesion Molecule-1 - metabolism; VLA-4 antigen; Xenografts
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/s41388-022-02233-w

Interferon regulatory factor 7 (IRF7) is widely studied in inflammatory models. Its effects on malignant progression have been documented mainly from the perspective of the microenvironment. However, its role in leukemia has not been established. Here we used MLL-AF9-induced acute myeloid leukemia (AML) mouse models with IRF7 knockout or overexpression and xenograft mouse models to explore the intrinsic effects of IRF7 in AML. AML-IRF7 −/− mice exhibited accelerated disease progression with intracerebral invasion of AML cells. AML-IRF7 −/− cells showed increased proliferation and elevated leukemia stem cell (LSC) levels. Overexpression of IRF7 in AML cells decreased cell proliferation and LSC levels. Furthermore, overexpression of transforming growth-interacting factor 1 (TGIF1) rescued the enhanced proliferation and high LSC levels caused by IRF7 deficiency. Moreover, upregulation of vascular cell adhesion molecule 1 (VCAM1), which correlated with high LSC levels, was detected in AML-IRF7 −/− cells. In addition, blocking VCAM1-very late antigen 4 (VLA-4) axis delayed disease progression and attenuated intracerebral invasion of AML cells. Therefore, our findings uncover the intrinsic effects of IRF7 in AML and provide a potential strategy to control central nervous system myeloid leukemia.