Abstract
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.
Highlights
Acute myeloid leukemia (AML) is characterized by the accumulation of a large number of immature myeloid cells [1] and differs from lymphoblastic leukemia in clinical feature and treatment [2, 3]
These results suggest that loss of Interferon regulatory factor 7 (IRF7) in AML cells promotes disease progression
Colony forming experiments showed that AML-IRF7-/--transforming growth-interacting factor 1 (TGIF1) cells formed fewer colonies than AML-IRF7−/ −-MSCV cells in primary and secondary plating experiment (Fig. 4I, Supplementary Fig. S6F). These results demonstrate that overexpression of TGIF1 rescues the enhanced proliferation and the high leukemia stem cell (LSC) level caused by IRF7 deficiency, which suggests that TGIF1 mediates those effects
Summary
Acute myeloid leukemia (AML) is characterized by the accumulation of a large number of immature myeloid cells [1] and differs from lymphoblastic leukemia in clinical feature and treatment [2, 3]. Both intrinsic and extrinsic abnormalities participate in the progression of AML [4, 5] by affecting the characteristics of the malignant population, including leukemia stem cell (LSC) levels [6], proliferation [7], dissemination, and infiltration [1], etc. The interferon regulatory factor (IRF) family contains 9 members (IRF1 to IRF9), which play pivotal roles in both innate and adaptive immunity [10] They act as intrinsic or microenvironmental factors in malignant progression [10, 11]. The intrinsic effects of IRF7 in AML remain unknown
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