OBJECTIVEAcute myeloid leukemia (AML) is an aggressive hematological malignancy with a poor prognosis. This study aimed to investigate the action of PARP14 in the growth and glycolysis of AML.METHODSThe clinical samples of AML patients were collected, and the expression of PARP14 was detected. AML cells were transfected with PARP14, HIF-1α or treated with NF-KB inhibitor (BAY11-7082) or PARP14 inhibitor (RBN012759). Cell proliferation was detected by CCK-8 and colony formation assays, apoptosis by flow cytometry, glucose consumption and lactate production by glucose and lactate kits, ECAR and OCR by XF96 bioenergy analyzer, and related protein levels by Western blot. A mouse xenograft tumor model was established to evaluate the effect of PARP14 on tumor formation.RESULTSSignificant upregulation of PARP14 expression was observed in AML. PARP14 promoted AML cell proliferation and glycolysis and inhibited apoptosis, while PARP14 deficiency had the opposite effect. PARP14 promoted HIF-1α expression by activating NF-κB. HIF-1α silencing reversed the cancer-promoting effect of PARP14. In vivo results suggested that PARP14 promoted tumor formation.CONCLUSIONPARP14 induces AML cell growth and glycolysis by activating NF-κB and promoting HIF-1α expression, which may suggest new insights into the pathogenesis of AML.

01 Jul 2022·ImmunoHorizons

Selective Pharmaceutical Inhibition of PARP14 Mitigates Allergen-Induced IgE and Mucus Overproduction in a Mouse Model of Pulmonary Allergic Response

Article

Author: Niepel, Mario ; Swinger, Kerren K. ; Molina, Jennifer R. ; Kunii, Kaiko ; Boothby, Mark R. ; Raybuck, Ariel L. ; Cho, Sung Hoon ; Chen, Kevin W. ; Keilhack, Heike ; Schenkel, Laurie B. ; Eddie, Alex M. ; Gibson-Corley, Katherine N. ; Peebles, R. Stokes

AbstractThe type 2 cytokines IL-4 and IL-13, which share use of an IL-4 receptor α-chain and its nuclear induction of the transcription factor STAT6, are crucial in elicitation and maintenance of allergic conditions including asthma. STAT6 binds poly(ADP-ribose) polymerase (PARP)14, an ADP-ribosyl monotransferase. Elimination of PARP14 by gene targeting led to attenuation of OVA-specific allergic lung inflammation. However, PARP14 has multiple functional domains apart from the portion that catalyzes ADP-ribosylation, and it is not clear whether inhibition of the catalytic function has any biological consequence. Using BALB/c mice sensitized to the allergen Alternaria alternata, we show that peroral administration of RBN012759, a highly selective inhibitor of ADP-ribosylation by PARP14 with negligible impact on other members of the PARP gene family, achieved biologically active plasma concentrations and altered several responses to the Ag. Specifically, the pharmaceutical compound decreased mucus after allergen challenge, blunted the induced increases in circulating IgE, and prevented suppression of IgG2a. We conclude that PARP14 catalytic activity can contribute to pathogenesis in allergic or atopic processes and propose that other biological endpoints dependent on ADP-ribosylation by PARP14 can be targeted using selective inhibition.

01 Aug 2021·Cell Chemical BiologyQ1 · BIOLOGY

A potent and selective PARP14 inhibitor decreases protumor macrophage gene expression and elicits inflammatory responses in tumor explants

Q1 · BIOLOGY

Article

Author: Vasbinder, Melissa M ; Kunii, Kaiko ; Richon, Victoria M ; Church, W David ; Reik, Christopher ; Lu, Alvin Z ; Ren, Yue ; Minissale, Elena ; Cheung, Anne E ; Mo, Jan-Rung ; Schenkel, Laurie B ; Keilhack, Heike ; Swinger, Kerren K ; Majer, Christina R ; Molina, Jennifer R ; Niepel, Mario ; Kuplast-Barr, Kristy G ; Blackwell, Danielle J ; Wigle, Tim J ; Abo, Ryan ; Kuntz, Kevin W

PARP14 has been implicated by genetic knockout studies to promote protumor macrophage polarization and suppress the antitumor inflammatory response due to its role in modulating interleukin-4 (IL-4) and interferon-γ signaling pathways. Here, we describe structure-based design efforts leading to the discovery of a potent and highly selective PARP14 chemical probe. RBN012759 inhibits PARP14 with a biochemical half-maximal inhibitory concentration of 0.003 μM, exhibits >300-fold selectivity over all PARP family members, and its profile enables further study of PARP14 biology and disease association both in vitro and in vivo. Inhibition of PARP14 with RBN012759 reverses IL-4-driven protumor gene expression in macrophages and induces an inflammatory mRNA signature similar to that induced by immune checkpoint inhibitor therapy in primary human tumor explants. These data support an immune suppressive role of PARP14 in tumors and suggest potential utility of PARP14 inhibitors in the treatment of cancer.

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Preclinical	US	Ribon Therapeutics, Inc.Startup	16 Apr 2020

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