SAMHD1 is a biomarker for cytarabine response and a therapeutic target in acute myeloid leukemia
The nucleoside analog cytarabine (Ara-C) is an essential component of primary and salvage chemotherapy regimens for acute myeloid leukemia (AML). After cellular uptake, Ara-C is converted into its therapeutically active triphosphate metabolite, Ara-CTP, which exerts antileukemic effects, primarily by inhibiting DNA synthesis in proliferating cells. Currently, a substantial fraction of patients with AML fail to respond effectively to Ara-C therapy, and reliable biomarkers for predicting the therapeutic response to Ara-C are lacking. SAMHD1 is a deoxynucleoside triphosphate (dNTP) triphosphohydrolase that cleaves physiological dNTPs into deoxyribonucleosides and inorganic triphosphate. Although it has been postulated that SAMHD1 sensitizes cancer cells to nucleoside-analog derivatives through the depletion of competing dNTPs, we show here that SAMHD1 reduces Ara-C cytotoxicity in AML cells. Mechanistically, dGTP-activated SAMHD1 hydrolyzes Ara-CTP, which results in a drastic reduction of Ara-CTP in leukemic cells. Loss of SAMHD1 activity-through genetic depletion, mutational inactivation of its triphosphohydrolase activity or proteasomal degradation using specialized, virus-like particles-potentiates the cytotoxicity of Ara-C in AML cells. In mouse models of retroviral AML transplantation, as well as in retrospective analyses of adult patients with AML, the response to Ara-C-containing therapy was inversely correlated with SAMHD1 expression. These results identify SAMHD1 as a potential biomarker for the stratification of patients with AML who might best respond to Ara-C-based therapy and as a target for treating Ara-C-refractory AML.
Errataetall: | |
---|---|
Medienart: |
E-Artikel |
Erscheinungsjahr: |
2017 |
---|---|
Erschienen: |
2017 |
Enthalten in: |
Zur Gesamtaufnahme - volume:23 |
---|---|
Enthalten in: |
Nature medicine - 23(2017), 2 vom: 19. Feb., Seite 250-255 |
Sprache: |
Englisch |
---|
Beteiligte Personen: |
Schneider, Constanze [VerfasserIn] |
---|
Links: |
---|
Anmerkungen: |
Date Completed 14.08.2017 Date Revised 13.11.2018 published: Print-Electronic ErratumIn: Nat Med. 2017 Jun 6;23 (6):788. - PMID 28586337 Citation Status MEDLINE |
---|
doi: |
10.1038/nm.4255 |
---|
funding: |
|
---|---|
Förderinstitution / Projekttitel: |
|
PPN (Katalog-ID): |
NLM26726416X |
---|
LEADER | 01000naa a22002652 4500 | ||
---|---|---|---|
001 | NLM26726416X | ||
003 | DE-627 | ||
005 | 20231224220311.0 | ||
007 | cr uuu---uuuuu | ||
008 | 231224s2017 xx |||||o 00| ||eng c | ||
024 | 7 | |a 10.1038/nm.4255 |2 doi | |
028 | 5 | 2 | |a pubmed24n0890.xml |
035 | |a (DE-627)NLM26726416X | ||
035 | |a (NLM)27991919 | ||
040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
041 | |a eng | ||
100 | 1 | |a Schneider, Constanze |e verfasserin |4 aut | |
245 | 1 | 0 | |a SAMHD1 is a biomarker for cytarabine response and a therapeutic target in acute myeloid leukemia |
264 | 1 | |c 2017 | |
336 | |a Text |b txt |2 rdacontent | ||
337 | |a ƒaComputermedien |b c |2 rdamedia | ||
338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
500 | |a Date Completed 14.08.2017 | ||
500 | |a Date Revised 13.11.2018 | ||
500 | |a published: Print-Electronic | ||
500 | |a ErratumIn: Nat Med. 2017 Jun 6;23 (6):788. - PMID 28586337 | ||
500 | |a Citation Status MEDLINE | ||
520 | |a The nucleoside analog cytarabine (Ara-C) is an essential component of primary and salvage chemotherapy regimens for acute myeloid leukemia (AML). After cellular uptake, Ara-C is converted into its therapeutically active triphosphate metabolite, Ara-CTP, which exerts antileukemic effects, primarily by inhibiting DNA synthesis in proliferating cells. Currently, a substantial fraction of patients with AML fail to respond effectively to Ara-C therapy, and reliable biomarkers for predicting the therapeutic response to Ara-C are lacking. SAMHD1 is a deoxynucleoside triphosphate (dNTP) triphosphohydrolase that cleaves physiological dNTPs into deoxyribonucleosides and inorganic triphosphate. Although it has been postulated that SAMHD1 sensitizes cancer cells to nucleoside-analog derivatives through the depletion of competing dNTPs, we show here that SAMHD1 reduces Ara-C cytotoxicity in AML cells. Mechanistically, dGTP-activated SAMHD1 hydrolyzes Ara-CTP, which results in a drastic reduction of Ara-CTP in leukemic cells. Loss of SAMHD1 activity-through genetic depletion, mutational inactivation of its triphosphohydrolase activity or proteasomal degradation using specialized, virus-like particles-potentiates the cytotoxicity of Ara-C in AML cells. In mouse models of retroviral AML transplantation, as well as in retrospective analyses of adult patients with AML, the response to Ara-C-containing therapy was inversely correlated with SAMHD1 expression. These results identify SAMHD1 as a potential biomarker for the stratification of patients with AML who might best respond to Ara-C-based therapy and as a target for treating Ara-C-refractory AML | ||
650 | 4 | |a Journal Article | |
650 | 7 | |a Antimetabolites, Antineoplastic |2 NLM | |
650 | 7 | |a Cytarabine |2 NLM | |
650 | 7 | |a 04079A1RDZ |2 NLM | |
650 | 7 | |a SAM Domain and HD Domain-Containing Protein 1 |2 NLM | |
650 | 7 | |a EC 3.1.5.- |2 NLM | |
650 | 7 | |a SAMHD1 protein, human |2 NLM | |
650 | 7 | |a EC 3.1.5.- |2 NLM | |
650 | 7 | |a Samhd1 protein, mouse |2 NLM | |
650 | 7 | |a EC 3.1.5.- |2 NLM | |
650 | 7 | |a Monomeric GTP-Binding Proteins |2 NLM | |
650 | 7 | |a EC 3.6.5.2 |2 NLM | |
650 | 7 | |a Daunorubicin |2 NLM | |
650 | 7 | |a ZS7284E0ZP |2 NLM | |
700 | 1 | |a Oellerich, Thomas |e verfasserin |4 aut | |
700 | 1 | |a Baldauf, Hanna-Mari |e verfasserin |4 aut | |
700 | 1 | |a Schwarz, Sarah-Marie |e verfasserin |4 aut | |
700 | 1 | |a Thomas, Dominique |e verfasserin |4 aut | |
700 | 1 | |a Flick, Robert |e verfasserin |4 aut | |
700 | 1 | |a Bohnenberger, Hanibal |e verfasserin |4 aut | |
700 | 1 | |a Kaderali, Lars |e verfasserin |4 aut | |
700 | 1 | |a Stegmann, Lena |e verfasserin |4 aut | |
700 | 1 | |a Cremer, Anjali |e verfasserin |4 aut | |
700 | 1 | |a Martin, Margarethe |e verfasserin |4 aut | |
700 | 1 | |a Lohmeyer, Julian |e verfasserin |4 aut | |
700 | 1 | |a Michaelis, Martin |e verfasserin |4 aut | |
700 | 1 | |a Hornung, Veit |e verfasserin |4 aut | |
700 | 1 | |a Schliemann, Christoph |e verfasserin |4 aut | |
700 | 1 | |a Berdel, Wolfgang E |e verfasserin |4 aut | |
700 | 1 | |a Hartmann, Wolfgang |e verfasserin |4 aut | |
700 | 1 | |a Wardelmann, Eva |e verfasserin |4 aut | |
700 | 1 | |a Comoglio, Federico |e verfasserin |4 aut | |
700 | 1 | |a Hansmann, Martin-Leo |e verfasserin |4 aut | |
700 | 1 | |a Yakunin, Alexander F |e verfasserin |4 aut | |
700 | 1 | |a Geisslinger, Gerd |e verfasserin |4 aut | |
700 | 1 | |a Ströbel, Philipp |e verfasserin |4 aut | |
700 | 1 | |a Ferreirós, Nerea |e verfasserin |4 aut | |
700 | 1 | |a Serve, Hubert |e verfasserin |4 aut | |
700 | 1 | |a Keppler, Oliver T |e verfasserin |4 aut | |
700 | 1 | |a Cinatl, Jindrich |c Jr |e verfasserin |4 aut | |
773 | 0 | 8 | |i Enthalten in |t Nature medicine |d 1995 |g 23(2017), 2 vom: 19. Feb., Seite 250-255 |w (DE-627)NLM074659804 |x 1546-170X |7 nnns |
773 | 1 | 8 | |g volume:23 |g year:2017 |g number:2 |g day:19 |g month:02 |g pages:250-255 |
856 | 4 | 0 | |u http://dx.doi.org/10.1038/nm.4255 |3 Volltext |
912 | |a GBV_USEFLAG_A | ||
912 | |a GBV_NLM | ||
951 | |a AR | ||
952 | |d 23 |j 2017 |e 2 |b 19 |c 02 |h 250-255 |