Identification of Nonfunctional Alternatively Spliced Isoforms of STING in Human Acute Myeloid Leukemia

Authors

Akash R Boda
Arthur J Liu
Susana Castro-Pando
Benjamin T Whitfield
Jeffrey J Molldrem
Gheath Al-Atrash
Maria Emilia Di Francesco
Philip Jones
Casey R Ager
Michael A Curran

Publication Date

3-25-2024

Journal

Cancer Research Communications

Abstract

UNLABELLED: Lack of robust activation of Stimulator of Interferon Genes (STING) pathway and subsequent induction of type I IFN responses is considered a barrier to antitumor immunity in acute myeloid leukemia (AML). Using common human AML cell lines as in vitro tools to evaluate the efficacy of novel STING agonists, we found most AML lines to be poor producers of IFNs upon exposure to extremely potent agonists, suggesting cell-intrinsic suppression of STING signaling may occur. We observed unexpected patterns of response that did not correlate with levels of STING pathway components or of known enzymes associated with resistance. To identify a genetic basis for these observations, we cloned and sequenced STING from the cDNA of human AML cell lines and found both frequent mutations and deviations from normal RNA splicing. We identified two novel spliced isoforms of STING in these lines and validated their expression in primary human AML samples. When transduced into reporter cells, these novel STING isoforms exhibited complete insensitivity to agonist stimulation. These observations identify alternative splicing as a mechanism of STING pathway suppression and suggest that most AML silences the STING pathway through direct modification rather than through engagement of external inhibitory factors.

SIGNIFICANCE: We find that AML acquires resistance to innate immune activation via the STING pathway through aberrant splicing of the STING transcript including two novel forms described herein that act as dominant negatives. These data broaden understanding of how cancers evolve STING resistance, and suggest that the AML tumor microenvironment, not the cancer cell, should be the target of therapeutic interventions to activate STING.

Keywords

Humans, Protein Isoforms, Leukemia, Myeloid, Acute, Alternative Splicing, Interferon Type I, Cell Line, Tumor Microenvironment

Comments

Supplementary Materials

PMID: 38477596