IRF8 Is an AML-Specific Susceptibility Factor That Regulates Signaling Pathways and Proliferation of AML Cells.

Franziska Liss,Ying Wang,Robert Liefke,Lisa Marie Weber,Andreas Neubauer,Andrea Nist,Andreas Burchert,Thorsten Stiewe,Clara Simon,Miriam Frech,Sabrina Fischer,Gavin Giel

doi:10.3390/cancers13040764

Abstract

Simple SummaryDespite progress, acute myeloid leukemia (AML) remains one of the deadliest cancer diseases. The identification of novel molecular targets may allow developing innovative and alternative treatment options for AML. Using public data from genome-edited cancer cells, we identified factors that are specifically essential for AML cell growth. We validated the critical role of the transcription factor IRF8 and demonstrated that it modulates the function of the cells by regulating important signaling molecules. These results support that IRF8 may be a suitable molecular target for the treatment of AML.Personalized treatment of acute myeloid leukemia (AML) that target individual aberrations strongly improved the survival of AML patients. However, AML is still one of the most lethal cancer diseases of the 21st century, demonstrating the need to find novel drug targets and to explore alternative treatment strategies. Upon investigation of public perturbation data, we identified the transcription factor IRF8 as a novel AML-specific susceptibility gene in humans. IRF8 is upregulated in a subset of AML cells and its deletion leads to impaired proliferation in those cells. Consistently, high IRF8 expression is associated with poorer patients’ prognoses. Combining gene expression changes upon IRF8 deletion and the genome-wide localization of IRF8 in the AML cell line MV4-11, we demonstrate that IRF8 directly regulates key signaling molecules, such as the kinases SRC and FAK, the transcription factors RUNX1 and IRF5, and the cell cycle regulator Cyclin D1. IRF8 loss impairs AML-driving signaling pathways, including the WNT, Chemokine, and VEGF signaling pathways. Additionally, many members of the focal adhesion pathway showed reduced expression, providing a putative link between high IRF8 expression and poor prognosis. Thus, this study suggests that IRF8 could serve as a biomarker and potential molecular target in a subset of human AMLs.

Highlights

Acute myeloid leukemia (AML) is a genetically heterogeneous myeloid disease caused by the hyperproliferation of undifferentiated myeloid progenitor cells [1]
AML could possibly be categorized into IRF8-dependent and IRF8-independent types. These results suggest that IRF8 upregulation in a subset of AML cells influences the properties of these cells, which in turn leads to a dependency on IRF8 for their proliferation
These results suggest that IRF8 upregulation in a subset of AML cells 8inofl2u0ences the properties of these cells, which in turn leads to a dependency on IRF8 for their proliferation

Summary

Introduction

Acute myeloid leukemia (AML) is a genetically heterogeneous myeloid disease caused by the hyperproliferation of undifferentiated myeloid progenitor cells [1]. Molecular lesions in AML cells occur mainly at two distinct levels: The activation of cytoplasmic tyrosine kinases (FLT3; KIT) or signaling modulators such as NRAS and secondary lesions that alter the function of certain transcription factors or epigenetic regulators, such as CEBPα, RUNX1, RUNX1T, RAR and KMT2A [1,4]. Identifying and understanding these genetic alterations allows the targeting of specific cellular pathways, such as the FLT3 kinase pathway, which is impaired in about 30% of all AML cases [5]. The common relapse of AML after first remission is most problematic [1]

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