Heterozygous colon cancer-associated mutations of
            <i>SAMHD1</i>
            have functional significance

Rentoft, Matilda; Lindell, Kristoffer; Tran, Phong; Chabes, Andrei; Buckland, Robert; Watt, Danielle L.; Marjavaara, Lisette; Nilsson, Agneta; Melin, Beatrice; Trygg, Johan; Johansson, Erik

doi:10.1073/pnas.1519128113

Cited by 105 publications

(173 citation statements)

References 67 publications

(76 reference statements)

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“…Underscoring a fundamental biologic role for SAMHD1, germ-line mutations in the gene encoding SAMHD1 are associated with human diseases, such as the neurodegenerative and hyperinflammatory Aicardi–Goutières syndrome (AGS) 6 . In addition, somatic aberrations of SAMHD1 have been found in chronic lymphocytic leukemia, 7 lung cancer, 8 and colorectal cancer 9 . More recently, we and others have identified SAMHD1 as an obstacle toward antimetabolite-based cancer therapies, 10-12 which will be the focus of this Extra View.…”

Section: Introductionmentioning

confidence: 99%

SAMHD1 protects cancer cells from various nucleoside-based antimetabolites

et al. 2017

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Recently, we demonstrated that sterile α motif and HD domain containing protein 1 (SAMHD1) is a major barrier in acute myelogenous leukemia (AML) cells to the cytotoxicity of cytarabine (ara-C), the most important drug in AML treatment. Ara-C is intracellularly converted by the canonical dNTP synthesis pathway to ara-CTP, which serves as a substrate but not an allosteric activator of SAMHD1. Using an AML mouse model, we show here that wild type but not catalytically inactive SAMHD1 reduces ara-C treatment efficacy in vivo. Expanding the clinically relevant substrates of SAMHD1, we demonstrate that THP-1 CRISPR/Cas9 cells lacking a functional SAMHD1 gene showed increased sensitivity to the antimetabolites nelarabine, fludarabine, decitabine, vidarabine, clofarabine, and trifluridine. Within this Extra View, we discuss and build upon both these and our previously reported findings, and propose SAMHD1 is likely active against a variety of nucleoside analog antimetabolites present in anti-cancer chemotherapies. Thus, SAMHD1 may constitute a promising target to improve a wide range of therapies for both hematological and non-haematological malignancies.

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Section: Introductionmentioning

confidence: 99%

SAMHD1 protects cancer cells from various nucleoside-based antimetabolites

et al. 2017

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“…Additionally, an imbalance to dNTP pools can lead to loss of genomic fidelity and impaired replication efficiency and accuracy (27–29, 199). It is therefore no surprise that recent studies have begun to implicate SAMHD1 in various cancers, including lymphocytic leukemia, lung adenocarcinoma, and colon cancer (106, 200–202) (Fig. 5).…”

Section: Samhd1 Mutations Results In Diseasementioning

confidence: 99%

“…Mutations in each region have been identified in patients with autoimmune disorders and cancer (178, 200, 201, 204). AGS mutations are believed to be causative loss-of-function resulting in dysregulation of nucleotide metabolism.…”

Section: Figurementioning

confidence: 99%

SAMHD1: Recurring roles in cell cycle, viral restriction, cancer, and innate immunity

Mauney

Hollis

2018

Autoimmunity

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SAMHD1 is a deoxynucleotide triphosphate (dNTP) hydrolase that plays an important role in the homeostatic balance of cellular dNTPs. Its emerging role as an effector of innate immunity is affirmed by mutations in the SAMHD1 gene that cause the severe autoimmune disease, Aicardi-Goutieres syndrome (AGS) and that are linked to cancer. Additionally, SAMHD1 functions as a restriction factor for retroviruses such as HIV. Here we review the current biochemical and biological properties of the enzyme including its structure, activity, and regulation by post-translational modifications in the context of its cellular function. We outline open questions regarding the biology of SAMHD1 whose answers will be important for understanding its function as a regulator of cell cycle progression, genomic integrity, and in autoimmunity.

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“…SAMHD1 may be a potential candidate tumor suppressor, as its function as a unique dNTPase places it at the intersection of cell cycle regulation, cellular proliferation, and mutagenesis [13, 14, 50, 51]. Heterozygous loss-of-function mutations in SAMHD1 are common in colon cancer and these mutants were determined to affect dNTP pools and increase mutation rates in colon cancer cells [52]. Mutations in the SAMHD1 gene have been identified as likely founder events in CLL [18], and a cohort of relapsed CLL patients had an 11% incidence of SAMHD1 mutations, as compared to a 3% incidence in the pre-treatment group [17].…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-181 contributes to downregulation of SAMHD1 expression in CD4+ T-cells derived from Sèzary syndrome patients

et al. 2017

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Sézary syndrome (SS) is a rare subtype of cutaneous T-cell lymphoma (CTCL) that is characterized by aggressive spread of neoplastic CD4+ T-cells from the skin into the bloodstream with metastasis to visceral organs. The deoxynucleoside triphosphohydrolase SAMHD1 is highly expressed in normal CD4+ T-cells, while its expression is down-regulated in CD4+ T-cells from SS patients. MicroRNA (miR) dysregulation is an important epigenetic mechanism in the pathogenesis and progression of SS. MiR-181 has been shown to inhibit SAMHD1 expression in cell lines and was identified as an important prognostic biomarker in CTCL. However, whether SAMHD1 is down-regulated by miR-181 in primary CD4+ T-cells of SS patients is unknown. Compared to normal CD4+ T-cells, SAMHD1 protein expression is significantly reduced in transformed CD4+ T-cell lines and CD4+ T-cells from SS patients, which inversely correlates with increased miR-181 levels in these cells. Over-expression of miR-181b in primary CD4+ T-cells from healthy donors significantly decreased SAMHD1 protein level, but not mRNA level. In contrast, inhibition of miR-181 in a CD4+ T-cell line significantly increased the level of SAMHD1 protein expression. Our results demonstrate that miR-181 is an important regulator of SAMHD1 protein expression in neoplastic CD4+ T-cells, likely through a mechanism of translational inhibition.

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Heterozygous colon cancer-associated mutations of SAMHD1 have functional significance

Cited by 105 publications

References 67 publications

SAMHD1 protects cancer cells from various nucleoside-based antimetabolites

SAMHD1 protects cancer cells from various nucleoside-based antimetabolites

SAMHD1: Recurring roles in cell cycle, viral restriction, cancer, and innate immunity

MicroRNA-181 contributes to downregulation of SAMHD1 expression in CD4+ T-cells derived from Sèzary syndrome patients

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