High <i>ENT1</i> and <i>DCK</i> gene expression levels are a potential biomarker to predict favorable response to nelarabine therapy in T‐cell acute lymphoblastic leukemia

Akahane, Koshi; Murakami, Yasushi; Kagami, Keiko; Abe, Masako; Harama, Daisuke; Shinohara, Tetsuji; Watanabe, Atsushi; Goi, Kumiko; Nishi, Rie; Yamauchi, Takahiro; Kimura, Shunsuke; Takita, Junko; Look, A. Thomas; Minegishi, Masayoshi; Sugita, Kanji; Inukai, Takeshi

doi:10.1002/hon.2654

Cited by 4 publications

(3 citation statements)

References 7 publications

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“…Moreover, T-ALL cells were characterised by substantially lower SAMHD1 levels than B-ALL cells. Previous studies had demonstrated an association between AraG efficacy and AraG triphosphate levels in leukaemia cells, but the mechanism determining AraG triphosphate levels had remained unknown [Verhoef and Fridland, 1985;Shewach andMitchell, 1989, Homminga et al, 2011;Akahane et al, 2019]. Hence, SAMHD1 is the missing link explaining the discrepancy in nelarabine sensitivity between T-ALL and B-ALL.…”

Section: Discussionmentioning

confidence: 99%

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

Rothenburger

McLaughlin

Herold

et al. 2019

Preprint

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The nucleoside analogue nelarabine, the prodrug of arabinosylguanine (AraG), has been known for decades to be effective against acute lymphoblastic leukaemias of T-cell (T-ALL), but not of B-cell (B-ALL) origin. The mechanisms underlying this lineage-specific drug sensitivity have remained elusive. Data from pharmacogenomics studies and from a panel of ALL cell lines revealed an inverse correlation of SAMHD1 expression and nelarabine sensitivity. SAMHD1 can hydrolyse and thus inactivate triphosphorylated nucleoside analogues. Transcriptomic and protein expression profiling of cell lines and patient-derived leukaemic blasts revealed lower SAMHD1 abundance in T-ALL than in B-ALL. Mechanistically, SAMHD1 promoter methylation strongly correlated with suppressed SAMHD1 expression, while T-ALL cells did not display increased global DNA methylation. Targeted SAMHD1 degradation using virus-like particles containing Vpx sensitised B-ALL cells to AraG, while ectopic SAMHD1 expression in SAMHD1-null T-ALL cells induced AraG resistance. SAMHD1had a larger impact on cytarabine activity than on nelarabine/ AraG activity in acute myeloid leukaemia (AML) cells, but more strongly affected nelarabine/ AraG activity in ALL cells. This indicates a critical role of the cancer entity. In conclusion, lineagespecific differences in SAMHD1 promoter methylation and, in turn, SAMHD1 expression levels determine ALL cell response to nelarabine. SAMHD1 is a potential biomarker for the identification of ALL patients likely to benefit from nelarabine therapy and a therapeutic target to overcome nelarabine resistance.Philadelphia chromosome-like acute lymphoblastic leukemia frequently have IGH-CRLF2 and JAK2 mutations, persistence of minimal residual disease and poor prognosis.

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Section: Discussionmentioning

confidence: 99%

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

Rothenburger

McLaughlin

Herold

et al. 2019

Preprint

View full text Add to dashboard Cite

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“…Nelarabine is a water-soluble pro-drug of arabinosylguanine (ara-G), a nucleoside metabolic inhibitor, indicated for the treatment of patients with T-cell ALL and T-cell lymphoblastic lymphoma [61]. The ara-G enters leukemic cells via ENT1 and ENT2 [104]. Evidence from bone marrow/peripheral blood samples from 96 pediatric acute leukemia patients untreated suggested that ara-G resistance could be mediated by a lower expression of ENT1 and ENT2 [103].…”

Section: Nelarabinementioning

confidence: 99%

“…Evidence from bone marrow/peripheral blood samples from 96 pediatric acute leukemia patients untreated suggested that ara-G resistance could be mediated by a lower expression of ENT1 and ENT2 [103]. An in vitro study found that SLC29A1 gene expression levels were highly associated with ara-G sensitivity in human T-ALL cell lines [104]. Neurotoxicity, the main adverse effect of nelarabine, requires the uptake of the drug into the neuronal cells; however, ENT's tole in elucidating this toxicity is unknown [131].…”

Section: Nelarabinementioning

confidence: 99%

Role of Drug Transporters in Elucidating Inter-Individual Variability in Pediatric Chemotherapy-Related Toxicities and Response

et al. 2022

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Pediatric cancer treatment has evolved significantly in recent decades. The implementation of risk stratification strategies and the selection of evidence-based chemotherapy combinations have improved survival outcomes. However, there is large interindividual variability in terms of chemotherapy-related toxicities and, sometimes, the response among this population. This variability is partly attributed to the functional variability of drug-metabolizing enzymes (DME) and drug transporters (DTS) involved in the process of absorption, distribution, metabolism and excretion (ADME). The DTS, being ubiquitous, affects drug disposition across membranes and has relevance in determining chemotherapy response in pediatric cancer patients. Among the factors affecting DTS function, ontogeny or maturation is important in the pediatric population. In this narrative review, we describe the role of drug uptake/efflux transporters in defining pediatric chemotherapy-treatment-related toxicities and responses. Developmental differences in DTS and the consequent implications are also briefly discussed for the most commonly used chemotherapeutic drugs in the pediatric population.

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

et al. 2020

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The nucleoside analogue nelarabine, the prodrug of arabinosylguanine (AraG), is effective against T-cell acute lymphoblastic leukaemia (T-ALL) but not against B-cell ALL (B-ALL). The underlying mechanisms have remained elusive. Here, data from pharmacogenomics studies and a panel of ALL cell lines reveal an inverse correlation between nelarabine sensitivity and the expression of SAMHD1, which can hydrolyse and inactivate triphosphorylated nucleoside analogues. Lower SAMHD1 abundance is detected in T-ALL than in B-ALL in cell lines and patient-derived leukaemic blasts. Mechanistically, T-ALL cells display increased SAMHD1 promoter methylation without increased global DNA methylation. SAMHD1 depletion sensitises B-ALL cells to AraG, while ectopic SAMHD1 expression in SAMHD1-null T-ALL cells induces AraG resistance. SAMHD1 has a larger impact on nelarabine/AraG than on cytarabine in ALL cells. Opposite effects are observed in acute myeloid leukaemia cells, indicating entity-specific differences. In conclusion, SAMHD1 promoter methylation and, in turn, SAMHD1 expression levels determine ALL cell response to nelarabine.

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High ENT1 and DCK gene expression levels are a potential biomarker to predict favorable response to nelarabine therapy in T‐cell acute lymphoblastic leukemia

Cited by 4 publications

References 7 publications

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

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

Role of Drug Transporters in Elucidating Inter-Individual Variability in Pediatric Chemotherapy-Related Toxicities and Response

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

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