SAMHD1 is a key regulator of the lineage-specific response of acute lymphoblastic leukaemias to nelarabine

Rothenburger, Tamara; McLaughlin, Katie-May; Herold, Tobias; Schneider, C.; Oellerich, Thomas; Rothweiler, Florian; Feber, Andrew; Fenton, Tim R.; Wass, Mark N.; Keppler, Oliver T.; Michaelis, Martin; Cinatl, Jindrich

doi:10.1101/863183

Cited by 3 publications

(2 citation statements)

References 56 publications

(40 reference statements)

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“…For example, targeting SAMHD1 by the Vpx protein has been found to benefit cytarabine therapy for hematological malignancies 39 . Moreover, SAMHD1 expression levels determine acute lymphoblastic leukemia cell response to nelarabine 40 .Therefore, these findings, along with our observations, suggest that SAMHD1 is a potential therapeutic target for improving chemotherapy efficacy in treating malignancies.…”

Section: Discussionsupporting

confidence: 70%

De-ubiquitination of SAMHD1 by USP7 overcomes oncogenic stress and contributes to chemotherapy insensitivity

Liu

Zhou²,

Dong³

et al. 2021

Preprint

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Oncogenic stress induces DNA damage response (DDR) that guards against genetic instability during the evolution of cancer. SAMHD1, a dNTPase protecting cells from viral infections, has been recently found to participate in DNA damage repair process. However, its role in tumorigenesis remains largely unknown. Here, we show that SAMHD1 is up-regulated in early-stage human carcinoma tissues and cell lines under oxidative stress or genotoxic insults. We further demonstrate that de-ubiquitinating enzyme USP7 interacts with SAMHD1 and de-ubiquitinates it at lysine 421, thus stabilizing SAMHD1 protein expression, and promotes tumor cell survival under genotoxic stress. Furthermore, SAMHD1 levels positively correlates with USP7 in various human carcinomas, and is associated with an unfavorable survival outcome in patients who underwent chemotherapy. Moreover, USP7 inhibitor sensitizes tumor cells to chemotherapeutic agents by decreasing SAMHD1 in vitro and in vivo. These findings suggest that targeting USP7 may help overcome chemoresistance, thus necessitating further investigation in the pursuit of precision medicine.

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Section: Discussionsupporting

confidence: 70%

De-ubiquitination of SAMHD1 by USP7 overcomes oncogenic stress and contributes to chemotherapy insensitivity

Liu

Zhou²,

Dong³

et al. 2021

Preprint

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show abstract

“…Nelarabine is the soluble prodrug of ara‐G, which is selectively cytotoxic to T leukaemic cells, likely due to their low endogenous SAMHD1 levels 29 . Initial early phase trials of nelarabine showed its efficacy as a single agent in paediatric relapsed/refractory T‐ALL, with neurotoxicity the most common dose‐limiting toxicity 30,31 .…”

Section: Nelarabinementioning

confidence: 99%

Current and emerging therapeutic approaches for T‐cell acute lymphoblastic leukaemia

et al. 2021

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Summary T‐cell ALL (T‐ALL) is an aggressive malignancy of T‐cell progenitors. Although survival outcomes in T‐ALL have greatly improved over the past 50 years, relapsed and refractory cases remain extremely challenging to treat and those who cannot tolerate intensive treatment continue to have poor outcomes. Furthermore, T‐ALL has proven a more challenging immunotherapeutic target than B‐ALL. In this review we explore our expanding knowledge of the basic biology of T‐ALL and how this is paving the way for repurposing established treatments and the development of novel therapeutic approaches.

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Dual roles of SAMHD1 in tumor development and chemoresistance to anticancer drugs (Review)

Chen

Shi

et al. 2021

Oncol Lett

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Human sterile alpha motif and HD-domaincontaining protein 1 (SAMHD1) has been identified as a GTP or dGTP-dependent deoxynucleotide triphosphohydrolase (dNTPase) and acts as an antiviral factor against certain retroviruses and DNA viruses. Genetic mutation in SAMHD1 causes the inflammatory Aicardi-Goutières Syndrome and abnormal intracellular deoxyribonucleoside triphosphates (dNTPs) pool. At present, the role of SAMHD1 in numerous types of cancer, such as chronic lymphocytic leukemia, lung cancer and colorectal cancer, is highly studied. Furthermore, it has been found that methylation, acetylation and phosphorylation are involved in the regulation of SAMHD1 expression, and that genetic mutations can cause changes in its activities, including dNTPase activity, long interspersed element type 1 (LINE-1) suppression and DNA damage repair, which could lead to uncontrolled cell cycle progression and cancer development. In addition, SAMHD1 has been reported to have a negative regulatory role in the chemosensitivity to anticancer drugs through its dNTPase activity. The present review aimed to summarize the regulation of SAMHD1 expression in cancer and its function in tumor growth and chemotherapy sensitivity, and discussed controversial points and future directions. Contents 1. Introduction 2. Role of methylation, acetylation and phosphorylation in the regulation of SAMHD1 expression in cancer 3. SAMHD1 inhibits the development of numerous types of tumor 4. SAMHD1 is a negative regulator of nucleotide analogs in vitro and in vivo. 5. Future directions and conclusion

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SAMHD1 is a key regulator of the lineage-specific response of acute lymphoblastic leukaemias to nelarabine

Cited by 3 publications

References 56 publications

De-ubiquitination of SAMHD1 by USP7 overcomes oncogenic stress and contributes to chemotherapy insensitivity

De-ubiquitination of SAMHD1 by USP7 overcomes oncogenic stress and contributes to chemotherapy insensitivity

Current and emerging therapeutic approaches for T‐cell acute lymphoblastic leukaemia

Dual roles of SAMHD1 in tumor development and chemoresistance to anticancer drugs (Review)

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