RNA Expression of Genes Involved in Cytarabine Metabolism and Transport Predicts Cytarabine Response in Acute Myeloid Leukemia

Abraham, Ajay; Varatharajan, Savitha; Karathedath, Sreeja; Philip, Chepsy C; Lakshmi, Kavitha M; Jayavelu, Ashok Kumar; Mohanan, Ezhilpavai; Janet, Nancy Beryl; Srivastava, Vivi M.; Shaji, R. V.; Zhang, Wei; Abraham, Aby; Viswabandya, Auro; George, Biju; Chandy, Mammen; Srivastava, Alok; Balasubramanian, Poonkuzhali

doi:10.2217/pgs.15.44

Cited by 38 publications

(29 citation statements)

References 46 publications

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“…phosphorylation) of Ara-C. These results would be in agreement with other studies [19] showing an in vitro correlation between hENT1 and DCK expression and nucleoside analogs sensitivity in pediatric and adult AML [18]. Recently, a collaborative EORTC-GIMEMA trial has demonstrated a better response rate and survival with high dose Ara-C in very high risk setting patients, including AML FLT3-ITD cases [22], that presumably would show high hENT1 expression according to our results.…”

Section: Discussionsupporting

confidence: 93%

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FLT3 is implicated in cytarabine transport by human equilibrative nucleoside transporter 1 in pediatric acute leukemia

et al. 2016

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FLT3 abnormalities are negative prognostic markers in acute leukemia. Infant leukemias are a subgroup with frequent MLL (KMT2A) rearrangements, FLT3 overexpression and high sensitivity to cytarabine, but dismal prognosis. Cytarabine is transported into cells by Human Equilibrative Nucleoside Transporter-1 (hENT1, SLC29A1), but the mechanisms that regulate hENT1 in acute leukemia have been scarcely studied.We explored the expression and functional link between FLT3 and main cytarabine transporters in 50 pediatric patients diagnosed with acute lymphoblastic leukemia and MLL rearrangement (ALL-MLL+) and other subtypes of leukemia, and in leukemia cell lines.A significant positive correlation was found between FLT3 and hENT1 expression in patients. Cytarabine uptake into cells was mediated mainly by hENT1, hENT2 and hCNT1. hENT1-mediated uptake of cytarabine was transiently abolished by the FLT3 inhibitor PKC412, and this effect was associated with decreased hENT1 mRNA and protein levels. Noticeably, the cytotoxicity of cytarabine was lower when cells were first exposed to FLT3 inhibitors (PKC412 or AC220), probably due to decreased hENT1 activity, but we observed a higher cytotoxic effect if FLT3 inhibitors were administered after cytarabine.FLT3 regulates hENT1 activity and thereby affects cytarabine cytotoxicity. The sequence of administration of cytarabine and FLT3 inhibitors is important to maintain their efficacy.

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Section: Discussionsupporting

confidence: 93%

“…Low levels of DCK tend to correlate with Ara-C resistance in childhood ALL and AML and adult AML [18, 30, 31]. Our observations suggest that DCK would not be a limiting step in Ara-CTP formation in patients with high FLT3 expression and thus, would support intracellular activation (i.e.…”

Section: Discussionmentioning

confidence: 85%

FLT3 is implicated in cytarabine transport by human equilibrative nucleoside transporter 1 in pediatric acute leukemia

et al. 2016

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“…As our screen only identified DCK as a candidate Ara-C resistance gene and defective DCK is already a known mechanism of Ara-C resistance489, we decided to remove the ability of the CRISPR library to knock out DCK . To avoid DCK gene modification by the CRISPR library, the 5 DCK gRNA targeted sites were modified in a cDNA of DCK by introducing silent mutations (Fig.…”

Section: Resultsmentioning

confidence: 99%

Using genome-wide CRISPR library screening with library resistant DCK to find new sources of Ara-C drug resistance in AML

Kurata

Rathe

Bailey

et al. 2016

Sci Rep

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Acute myeloid leukemia (AML) can display de novo or acquired resistance to cytosine arabinoside (Ara-C), a primary component of induction chemotherapy. To identify genes capable of independently imposing Ara-C resistance, we applied a genome-wide CRISPR library to human U937 cells and exposed to them to Ara-C. Interestingly, all drug resistant clones contained guide RNAs for DCK. To avoid DCK gene modification, gRNA resistant DCK cDNA was created by the introduction of silent mutations. The CRISPR screening was repeated using the gRNA resistant DCK, and loss of SLC29A was identified as also being capable of conveying Ara-C drug resistance. To determine if loss of Dck results in increased sensitivity to other drugs, we conducted a screen of 446 FDA approved drugs using two Dck-defective BXH-2 derived murine AML cell lines and their Ara-C sensitive parental lines. Both cell lines showed an increase in sensitivity to prednisolone. Guide RNA resistant cDNA rescue was a legitimate strategy and multiple DCK or SLC29A deficient human cell clones were established with one clone becoming prednisolone sensitive. Dck-defective leukemic cells may become prednisolone sensitive indicating prednisolone may be an effective adjuvant therapy in some cases of DCK-negative AML.

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“…Because the uptake of cytarabine in leukemic blasts is highly sensitive to NBMPR, it has been assumed and asserted for several decades that cytarabine enters cells through an ENT1-dependent mechanism (1). This conclusion is supported by some (10, 11) but not all statistical association studies (12–14), indicating that increased ENT1 mRNA abundance is correlated with increased cellular sensitivity or clinical responsiveness to cytarabine. More importantly, however, published studies to date employing heterologous expression systems have shown that cytarabine is either very weakly transported by ENT1 (<2-fold vs control) (15, 16) or is not transported by ENT1 at all (17).…”

Section: Introductionmentioning

confidence: 87%

OCTN1 Is a High-Affinity Carrier of Nucleoside Analogues

et al. 2017

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Resistance to xenobiotic nucleosides used to treat acute myeloid leukemia (AML) and other cancers remains a major obstacle to clinical management. One process suggested to participate in resistance is reduced uptake into tumor cells via nucleoside transporters, although precise mechanisms are not understood. Through transcriptomic profiling, we determined that low expression of the ergothioneine transporter OCTN1 (SLC22A4; ETT) strongly predicts poor event-free survival and overall survival in multiple cohorts of AML patients receiving treatment with the cytidine nucleoside analog cytarabine. Cell biological studies confirmed OCTN1-mediated transport of cytarabine and various structurally-related cytidine analogs, such as 2′deoxycytidine and gemcitabine, occurs through a saturable process that is highly sensitive to inhibition by the classic nucleoside transporter inhibitors dipyridamole and nitrobenzylmercaptopurine ribonucleoside (NBMPR). Our findings have immediate clinical implications given the potential of the identified transport system to help refine strategies that could improve patient survival across multiple cancer types where nucleoside analogs are used in cancer treatment.

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RNA Expression of Genes Involved in Cytarabine Metabolism and Transport Predicts Cytarabine Response in Acute Myeloid Leukemia

Cited by 38 publications

References 46 publications

FLT3 is implicated in cytarabine transport by human equilibrative nucleoside transporter 1 in pediatric acute leukemia

FLT3 is implicated in cytarabine transport by human equilibrative nucleoside transporter 1 in pediatric acute leukemia

Using genome-wide CRISPR library screening with library resistant DCK to find new sources of Ara-C drug resistance in AML

OCTN1 Is a High-Affinity Carrier of Nucleoside Analogues

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