Schlafen 11 expression in human acute leukemia cells with gain-of-function mutations in the interferon-JAK signaling pathway

Yasuhisa Murai; Ukhyun Jo; Junko Murai; Shinsaku Fukuda; Naoko Takebe; Yves Pommier

doi:10.1016/j.isci.2021.103173

Schlafen 11 expression in human acute leukemia cells with gain-of-function mutations in the interferon-JAK signaling pathway

iScience. 2021 Sep 25;24(10):103173. doi: 10.1016/j.isci.2021.103173. eCollection 2021 Oct 22.

Authors

Yasuhisa Murai^{1

2}, Ukhyun Jo¹, Junko Murai³, Shinsaku Fukuda², Naoko Takebe^{1

4}, Yves Pommier¹

Affiliations

¹ Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA.
² Department of Gastroenterology and Hematology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
³ Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata, Japan.
⁴ Developmental Therapeutics Branch and Division of Cancer Treatment and Diagnosis, National Cancer Institute, NIH, Bethesda, MD, USA.

Abstract

Schlafen11 (SLFN11) is referred to as interferon (IFN)-inducible. Based on cancer genomic databases, we identified human acute myeloid and lymphoblastic leukemia cells with gain-of-function mutations in the Janus kinase (JAK) family as exhibiting high SLFN11 expression. In these cells, the clinical JAK inhibitors cerdulatinib, ruxolitinib, and tofacitinib reduced SLFN11 expression, but IFN did not further induce SLFN11 despite phosphorylated STAT1. We provide evidence that suppression of SLFN11 by JAK inhibitors is caused by inactivation of the non-canonical IFN pathway controlled by AKT and ERK. Accordingly, the AKT and ERK inhibitors MK-2206 and SCH77284 suppressed SLFN11 expression. Both also suppressed the E26 transformation-specific (ETS)-family genes ETS-1 and FLI-1 that act as transcription factors for SLFN11. Moreover, SLFN11 expression was inhibited by the ETS inhibitor TK216. Our study reveals that SLFN11 expression is regulated via the JAK, AKT and ERK, and ETS axis. Pharmacological suppression of SLFN11 warrants future studies.

Keywords: Cell biology; Immunology; Molecular biology.