Myelodysplastic syndrome-associated spliceosome gene mutations enhance innate immune signaling

Abstract

Myelodysplastic syndrome-associated spliceosome gene mutations enhance innate immune signaling Genes encoding spliceosome components including SF3B1, U2AF1, and SRSF2, are frequently somatically mutated in myelodysplastic syndromes (MDS), other hematologic malignancies, and solid tumors. 1 Typically these are mutually exclusive, heterozygous, missense, hotspot mutations that result in neomorphic or gain-offunction splicing phenotypes. These mutations alter splicing of many genes; however, overlap among the different splicing factors is limited. Thus, a common mechanism by which spliceosome mutations contribute to disease is suspected but has remained elusive. We previously demonstrated that inhibiting any of five different spliceosome genes (SF3B1, SF3A1, SF3A2, SF3A3, EFTUD2) in mouse or human macrophages reduces inflammatory cytokine production induced by multiple Toll-like receptor (TLR) agonists including the TLR4 agonist lipopolysaccharide (LPS). 2-5 Although these genes encode essential spliceosome components, partial gene knockdown (approx. 80%) reduces LPS-induced inflammatory cytokine production without affecting viability or phagocytosis. 2-5 Hence, innate immunity may be particularly sensitive to spliceosome perturbation. These observations suggest that MDS-associated spliceosome mutations might enhance innate immunity,

NF-κB mediates lipopolysaccharide-induced alternative pre-mRNA splicing of MyD88 in mouse macrophages

“…While these are essential splicing factors, inhibition at around the 80% level weakened LPS-induced inflammatory cytokine production without affecting cell viability (12,44,45). This weakened response to LPS was caused, in part, by increased production of MyD88-S when the spliceosome was inhibited (12,44,45). We further showed that moderate inhibition of the spliceosome had relatively specific effects,…”

“…We have previously shown that inhibition of core components of the spliceosome (SF3A1, SF3A2, SF3A3, SF3B1, or U2AF1) weakens the response to LPS in mouse and/or human macrophages (12,44,45). These core spliceosome factors all bind to the 3' end of introns to facilitate pre-mRNA splicing (46)(47)(48)(49).…”

“…These core spliceosome factors all bind to the 3' end of introns to facilitate pre-mRNA splicing (46)(47)(48)(49). While these are essential splicing factors, inhibition at around the 80% level weakened LPS-induced inflammatory cytokine production without affecting cell viability (12,44,45). This weakened response to LPS was caused, in part, by increased production of MyD88-S when the spliceosome was inhibited (12,44,45).…”

CtIP -mediated alternative mRNA splicing finetunes the DNA damage response

“…However, considering the involvement of CtIP, described here, and BRCA1 (Savage et al, 2014) in RNA splicing, maybe the cancer connection should be revisited on the light of those novel roles. Conversely, recent studies have detected recurrent mutations in components of the spliceosome in myelodysplastic syndromes (Pollyea et al, 2019; Shiozawa et al, 2018), renal cell carcinoma (Verma and Das, 2018; Yang et al, 2017), chronic lymphocytic leukaemia (Agrawal et al, 2017; Maleki et al, 2019), lung adenocarcinoma (Kim et al, 2018; Mao et al, 2019), breast cancer (Gokmen-Polar et al, 2019; Zhao et al, 2019) or pancreatic cancer (Tian et al, 2015; Zhou et al, 2017). Moreover, alterations in expression of splicing factors, including SF3B, can derive in various types of cancers (Alsafadi et al, 2016; Goswami et al, 2014; Maguire et al, 2015; Zheng et al, 2018).…”

Contribution of Aberrant Toll Like Receptor Signaling to the Pathogenesis of Myelodysplastic Syndromes

“…For example, Smith et al (76) found that the expression of a longer isoform of IRAK4 (IRAK4-L), which is associated with enhanced activation of NF-kB and leukemic transformation, is mediated by mutant forms of the splicing factor U2 small nuclear RNA auxiliary factor 1 (U2AF1). Similarly, Alper et al (77)(78)(79) showed that inhibition of spliceosome genes reduces inflammatory cytokine production in response to TLR agonists, and conversely, expression of MDS-associated spliceosome mutations (involving splicing factors U2AF1, SF3B1, or SRSF2) enhances NF-κB activity and cytokine production by K562 myeloid leukemia cells following TLR stimulation. Mechanistically, the spliceosome mutations alter the splicing of genes that regulate TLR signaling and promote NF-κB activation, including MAP3K7 and CASP8 (77).…”