Human APOBEC3 proteins play pivotal roles in intracellular defense against viral infection by catalyzing deamination of cytidine residues, leading to base substitutions in viral DNA. Activation-induced cytidine deaminase (AID), another member of the APOBEC family, is capable of editing immunoglobulin (Ig) and non-Ig genes, and aberrant expression of AID leads to tumorigenesis. However, it remains unclear whether APOBEC3 (A3) proteins affect stability of human genome. Here we demonstrate that both A3A and A3B can induce base substitutions into human genome as AID can. A3B is highly expressed in several lymphoma cells and somatic mutations occur in some oncogenes of the cells highly expressing A3B. Furthermore, transfection of A3B gene into lymphoma cells induces base substitutions in cMYC gene. These data suggest that aberrant expression of A3B can evoke genomic instability by inducing base substitutions into human genome, which might lead to tumorigenesis in human cells.

Acute myeloid leukemia (AML) pathogenesis often involves a mutation in the NPM1 nucleolar chaperone, but the bases for its transforming properties and overall association with favorable therapeutic responses remain incompletely understood. Here we demonstrate that an oncogenic mutant form of NPM1 (NPM1c) impairs mitochondrial function. NPM1c also hampers formation of PML nuclear bodies (NBs), which are regulators of mitochondrial fitness and key senescence effectors. Actinomycin D (ActD), an antibiotic with unambiguous clinical efficacy in relapsed/refractory NPM1c-AMLs, targets these primed mitochondria, releasing mtDNA, activating cGAS signaling and boosting ROS production. The latter restore PML NB formation to drive TP53 activation and senescence of NPM1c-AML cells. In several models, dual targeting of mitochondria by venetoclax and ActD synergized to clear AML and prolong survival through targeting of PML. Our studies reveal an unexpected role for mitochondria downstream of NPM1c and implicate a mitochondrial/ROS/PML/TP53 senescence pathway as an effector of ActD-based therapies. SIGNIFICANCEActinomycin D induces complete remissions in NPM1-mutant AMLs. We found that NPM1c affects mitochondrial biogenesis and PML bodies (NBs).Actinomycin D targets mitochondria, yielding ROS which enforce PML NB-biogenesis and restore senescence. Dual targeting of mitochondria with actinomycin D and venetoclax sharply potentiates their anti-AML activities in vivo.Research.

The case histories of 124 children irradiated for brain tumors were reviewed to determine survival rate and functional prognosis, with special reference to somatic growth. Five-year survival rates (29% of 97 patients with gliomas and 70% of 27 patients with non-gliomatous tumors) were approximately the same as in our adult series, despite the differences in histology and predilection. Although 70% of 42 long-term survivors had active, useful lives, stunted growth was observed in 15 of them. More attention should be directed to the growth of children irradiated for brain tumors.

An anti–HIV-1 drug is found to destroy leukemia cells in adults.

Adult T‐cell leukemia (ATL) has a poor prognosis as a result of severe immunosuppression and rapid tumor progression with resistance to conventional chemotherapy. Recent integrated‐genome analysis has revealed mutations in many genes involved in the T‐cell signaling pathway, suggesting that the aberration of this pathway is an important factor in ATL pathogenesis and ATL‐cell proliferation. We screened a siRNA library to examine signaling‐pathway functionality and found that the PI3K/Akt/mTOR pathway is critical to ATL‐cell proliferation. We therefore investigated the effect of mammalian target of rapamycin (mTOR) inhibitors, including the dual inhibitors PP242 and AZD8055 and the mTORC1 inhibitors rapamycin and everolimus, on human T‐cell leukemia virus type 1 (HTLV‐1)‐infected‐cell and ATL‐cell lines. Both dual inhibitors inhibited the proliferation of all tested cell lines by inducing G1‐phase cell‐cycle arrest and subsequent cell apoptosis, whereas the effects of the 2 mTORC1 inhibitors were limited, as they did not induce cell apoptosis. In the ATL‐cell lines and in the primary ATL samples, both dual inhibitors inhibited phosphorylation of AKT at serine‐473, a target of mTORC2, as well as that of S6K, whereas the mTORC1 inhibitors only inhibited mTORC1. Furthermore, AZD8055 more significantly inhibited the in vivo growth of the ATL‐cell xenografts than did everolimus. These results indicate that the PI3K/mTOR pathway is critical to ATL‐cell proliferation and might thus be a new therapeutic target in ATL.

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The transcription factor NF-κB plays a key regulatory role in lymphocyte activation and generation of immune response. Stimulation of T cell receptor (TCR) induces phosphorylation of CARMA1 by PKCθ, resulting in formation of CARMA1-Bcl10-MALT1 (CBM) complex at lipid rafts and subsequently leading to NF-κB activation. While many molecular events leading to NF-κB activation have been reported, it is less understood how this activation is negatively regulated. We performed a cell-based screening for negative regulators of TCR-mediated NF-κB activation, using mutagenesis and complementation cloning strategies. Here we show that casein kinase-2 interacting protein-1 (CKIP-1) suppresses PKCθ-CBM-NF-κB signaling. We found that CKIP-1 interacts with CARMA1 and competes with PKCθ for association. We further confirmed that a PH domain of CKIP-1 is required for association with CARMA1 and its inhibitory effect. CKIP-1 represses NF-κB activity in unstimulated cells, and inhibits NF-κB activation induced by stimulation with PMA or constitutively active PKCθ, but not by stimulation with TNFα. Interestingly, CKIP-1 does not inhibit NF-κB activation induced by CD3/CD28 costimulation, which caused dissociation of CKIP-1 from lipid rafts. These data suggest that CKIP-1 contributes maintenance of a resting state on NF-κB activity or prevents T cells from being activated by inadequate signaling. In conclusion, we demonstrate that CKIP-1 interacts with CARMA1 and has an inhibitory effect on PKCθ-CBM-NF-κB signaling.

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