PKR inhibits the DNA damage response, and is associated with poor survival in AML and accelerated leukemia in NHD13 mice

Abstract

• Nuclear PKR activity represses DNA damage response signaling and DNA repair in primary hematopoietic cells.• Increased PKR promotes genomic instability and inferior outcomes in both AML and the NHD13 mouse model of leukemia.Increased expression of the interferon-inducible double-stranded RNA-activated protein kinase (PKR) has been reported in acute leukemia and solid tumors, but the role of PKR has been unclear. Now, our results indicate that high PKR expression in CD34 1 cells of acute myeloid leukemia (AML) patients correlates with worse survival and shortened remission duration. Significantly, we find that PKR has a novel and previously unrecognized nuclear function to inhibit DNA damage response signaling and double-strand break repair. Nuclear PKR antagonizes ataxia-telangiectasia mutated (ATM) activation by a mechanism dependent on protein phosphatase 2A activity. Thus, inhibition of PKR expression or activity promotes ATM activation, g-H2AX formation, and phosphorylation of NBS1 following ionizing irradiation. PKR transgenic but not PKR null mice demonstrate a mutator phenotype characterized by radiation-induced and age-associated genomic instability that was partially reversed by short-term pharmacologic PKR inhibition. Furthermore, the ageassociated accumulation of somatic mutations that occurs in the Nup98-HOXD13 (NHD13) mouse model of leukemia progression was significantly elevated by co-expression of a PKR transgene, whereas knockout of PKR expression or pharmacologic inhibition of PKR activity reduced the frequency of spontaneous mutations in vivo. Thus, PKR cooperated with the NHD13 transgene to accelerate leukemia progression and shorten survival. Taken together, these results indicate that increased nuclear PKR has an oncogenic function that promotes the accumulation of potentially deleterious mutations. Thus, PKR inhibition may be a therapeutically useful strategy to prevent leukemia progression or relapse, and improve clinical outcomes. (Blood. 2015;126(13):1585-1594

Overexpression of HOXA10 is associated with unfavorable prognosis of acute myeloid leukemia

“…Also EIF2AK2 is the only EIF2α kinase exists in both the cytoplasm and nucleolus, while other 3 kinases present only in the cytoplasm(68). Cheng X et al reported that high expression of EIF2AK2 was associated with worse prognosis in AML, and it reduced DNA damage response by inhibiting ataxiatelangiectasia mutated (ATM) activation, leading to accretion of leukemia in mice model (69). EIF2AK3 (also named as PKR-like endoplasmic reticulum kinase, PERK) is reported to promoted leukemia progress by stimulating the dissemination of leukemia cells in vivo (70).…”

Protein Phosphatase 2A as a Therapeutic Target in Acute Myeloid Leukemia

“…PR55α/B55α also supports expression of miR-142-3p and suppresses expression of miR-191-5p, relevant miRNAs in AML ( 17 ). DNA damage response is impaired by dephosphorylation of ATM by PP2A-PR55α/B55α, which translocate to the nucleus by PKR ( 18 ). Extracellular survival signals activate SRC that suppresses the B subunit; when SRC is suppressed, PR55α/B55α is expressed, resulting in dephosphorylation of PKCα and suppression of PR61α/B56α protein expression, with concomitant induction of MYC ( 19 ).…”

Discriminating Self and Non-Self by RNA: Roles for RNA Structure, Misfolding, and Modification in Regulating the Innate Immune Sensor PKR

“…12 Although PKR is primarily found in the cytoplasm where it regulates translation, about 20% of PKR is nuclear where it has been shown to regulate RNA splicing, mRNA stability, and ribosome biogenesis and affect diseases including acute myeloid leukemia AML. 16–18 …”