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:10.1038/s42003-020-1052-8

Cited by 25 publications

(31 citation statements)

References 50 publications

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“…The former processes thus naturally ensure deeper and more solid encoding via the active process of making notes. Moreover, it has been reported that longhand note-taking enhanced the performance of students on recognition of memorized words, even though typing on a computer keyboard allowed greater speed (Aragón-Mendizábal et al, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

Paper Notebooks vs. Mobile Devices: Brain Activation Differences During Memory Retrieval

Umejima

Ibaraki²,

Yamazaki³

et al. 2021

Front. Behav. Neurosci.

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It remains to be determined how different inputs for memory-encoding, such as the use of paper notebooks or mobile devices, affect retrieval processes. We compared three groups of participants who read dialogues on personal schedules and wrote down the scheduled appointments on a calendar using a paper notebook (Note), an electronic tablet (Tablet), or a smartphone (Phone). After the retention period for an hour including an interference task, we tested recognition memory of those appointments with visually presented questions in a retrieval task, while scanned with functional magnetic resonance imaging. We obtained three major results. First, the duration of writing down schedules was significantly shorter for the Note group than the Tablet and Phone groups, and accuracy was much higher for the Note group in easier (i.e., more straightforward) questions. Because the input methods were equated as much as possible between the Note and Tablet groups, these results indicate that the cognitive processes for the Note group were deeper and more solid. Second, brain activations for all participants during the retrieval phase were localized in the bilateral hippocampus, precuneus, visual cortices, and language-related frontal regions, confirming the involvement of verbalized memory retrieval processes for appointments. Third, activations in these regions were significantly higher for the Note group than those for the Tablet and Phone groups. These enhanced activations for the Note group could not be explained by general cognitive loads or task difficulty, because overall task performances were similar among the groups. The significant superiority in both accuracy and activations for the Note group suggested that the use of a paper notebook promoted the acquisition of rich encoding information and/or spatial information of real papers and that this information could be utilized as effective retrieval clues, leading to higher activations in these specific regions.

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Section: Introductionmentioning

confidence: 99%

Paper Notebooks vs. Mobile Devices: Brain Activation Differences During Memory Retrieval

Umejima

Ibaraki²,

Yamazaki³

et al. 2021

Front. Behav. Neurosci.

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“…In a recent study, a combined pharmacogenomics data combined with data from an ALL cell line panel and patients reported the sensitivity differences between T-ALL and B-ALL. It was seen that the depletion of the deoxynucleotide triphosphate (dNTP) hydrolase SAMHD1, that is able to cleave and inactivate AraG, sensitized ALL cells to AraG, underlining the role as a therapeutic target to improve nelarabine therapies in ALL patients ( 117 ).…”

Section: Therapeutic Options Targeting the Microenvironment In All: Focus On Some Recent Therapiesmentioning

confidence: 99%

The Complexity of the Tumor Microenvironment and Its Role in Acute Lymphoblastic Leukemia: Implications for Therapies

et al. 2021

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The microenvironment that surrounds a tumor, in addition to the tumor itself, plays an important role in the onset of resistance to molecularly targeted therapies. Cancer cells and their microenvironment interact closely between them by means of a molecular communication that mutually influences their biological characteristics and behavior. Leukemia cells regulate the recruitment, activation and program of the cells of the surrounding microenvironment, including those of the immune system. Studies on the interactions between the bone marrow (BM) microenvironment and Acute Lymphoblastic Leukemia (ALL) cells have opened a scenario of potential therapeutic targets which include cytokines and their receptors, signal transduction networks, and hypoxia-related proteins. Hypoxia also enhances the formation of new blood vessels, and several studies show how angiogenesis could have a key role in the pathogenesis of ALL. Knowledge of the molecular mechanisms underlying tumor-microenvironment communication and angiogenesis could contribute to the early diagnosis of leukemia and to personalized molecular therapies. This article is part of a Special Issue entitled: Innovative Multi-Disciplinary Approaches for Precision Studies in Leukemia edited by Sandra Marmiroli (University of Modena and Reggio Emilia, Modena, Italy) and Xu Huang (University of Glasgow, Glasgow, United Kingdom).

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“…Sterile alpha motif and histidine-aspartate domain-containing protein 1 (SAMHD1) is a deoxynucleoside triphosphate (dNTP) triphosphohydrolase that cleaves physiological dNTPs into deoxyribonucleotides and inorganic triphosphate [Goldstone et al, 2011;Powell et al, 2011]. SAMHD1 also inactivates the triphosphorylated forms of some anti-cancer nucleoside analogues [Schneider et al, 2017;Herold et al, 2017;Knecht et al, 2018;Oellerich et al, 2019;Rothenburger et al, 2020;Xagoraris et al, 2021]. High SAMHD1 levels indicate poor clinical response to nucleoside analogues such as cytarabine, decitabine, and nelarabine in acute myeloid leukaemia (AML), acute lymphoblastic leukaemia, and Hodgkin lymphoma [Schneider et al, 2017;Oellerich et al, 2019;Rothenburger et al, 2020;Xagoraris et al, 2021].…”

Section: Introductionmentioning

confidence: 99%

“…SAMHD1 also inactivates the triphosphorylated forms of some anti-cancer nucleoside analogues [Schneider et al, 2017;Herold et al, 2017;Knecht et al, 2018;Oellerich et al, 2019;Rothenburger et al, 2020;Xagoraris et al, 2021]. High SAMHD1 levels indicate poor clinical response to nucleoside analogues such as cytarabine, decitabine, and nelarabine in acute myeloid leukaemia (AML), acute lymphoblastic leukaemia, and Hodgkin lymphoma [Schneider et al, 2017;Oellerich et al, 2019;Rothenburger et al, 2020;Xagoraris et al, 2021]. Moreover, previous findings indicated differing roles of SAMHD1 in intrinsic and acquired resistance to nucleoside analogues [Schneider et al, 2017;Oellerich et al, 2019].…”

Section: Introductionmentioning

confidence: 99%

Differences between intrinsic and acquired nucleoside analogue resistance in acute myeloid leukaemia cells

Rothenburger

Thomas

Schreiber

et al. 2021

Preprint

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Background: SAMHD1 mediates resistance to anti-cancer nucleoside analogues, including cytarabine, decitabine, and nelarabine that are commonly used for the treatment of leukaemia, through cleavage of their triphosphorylated forms. Hence, SAMHD1 inhibitors are promising candidates for the sensitisation of leukaemia cells to nucleoside analogue-based therapy. Here, we investigated the effects of the cytosine analogue CNDAC, which has been proposed to be a SAMHD1 substrate, in the context of SAMHD1. Methods: CNDAC was tested in 13 acute myeloid leukaemia (AML cell lines), in 26 acute lymphoblastic leukaemia cell lines, ten AML sublines adapted to various antileukaemic drugs, 24 single cell-derived clonal AML sublines, and primary leukaemic blasts from 24 AML patients. Moreover, 24 CNDAC-resistant sublines of the AML cell lines HL-60 and PL-21 were established. The SAMHD1 gene was disrupted using CRISPR/Cas9 and SAMHD1 depleted using RNAi, and the viral Vpx protein. Forced DCK expression was achieved by lentiviral transduction. SAMHD1 promoter methylation was determined by PCR after treatment of genomic DNA with the methylation-sensitive HpaII endonuclease. Nucleoside (analogue) triphosphate levels were determined by LC-MS/MS. CNDAC interaction with SAMHD1 was analysed by an enzymatic assay and by crystallisation. Results: Although the cytosine analogue CNDAC was anticipated to inhibit SAMHD1, SAMHD1 mediated intrinsic CNDAC resistance in leukaemia cells. Accordingly, SAMHD1 depletion increased CNDAC triphosphate (CNDAC-TP) levels and CNDAC toxicity. Enzymatic assays and crystallisation studies confirmed CNDAC-TP to be a SAMHD1 substrate. In 24 CNDAC-adapted acute myeloid leukaemia (AML) sublines, resistance was driven by DCK (catalyses initial nucleoside phosphorylation) loss. CNDAC-adapted sublines displayed cross-resistance only to other DCK substrates (e.g. cytarabine, decitabine). Cell lines adapted to drugs not affected by DCK or SAMHD1 remained CNDAC sensitive. In cytarabine-adapted AML cells, increased SAMHD1 and reduced DCK levels contributed to cytarabine and CNDAC resistance. Conclusion: Intrinsic and acquired resistance to CNDAC and related nucleoside analogues are driven by different mechanisms. The lack of cross-resistance between SAMHD1/ DCK substrates and non-substrates provides scope for next-line therapies after treatment failure.

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

Cited by 25 publications

References 50 publications

Paper Notebooks vs. Mobile Devices: Brain Activation Differences During Memory Retrieval

Paper Notebooks vs. Mobile Devices: Brain Activation Differences During Memory Retrieval

The Complexity of the Tumor Microenvironment and Its Role in Acute Lymphoblastic Leukemia: Implications for Therapies

Differences between intrinsic and acquired nucleoside analogue resistance in acute myeloid leukaemia cells

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