Targeting IMPDH to inhibit SAMHD1 in KMT2A-rearranged leukaemia

Cytarabine (ara-C) and fludarabine (F-ara-A) are key drugs in leukaemia treatment. SAMHD1 is known to confer resistance to ara-C and F-ara-A, and we previously identified ribonucleotide reductase inhibitors as indirect SAMHD1 inhibitors in a phenotypic screen. The inosine monophosphate dehydrogenase...

Descripción completa

Detalles Bibliográficos
Autores: Klootsema, Yolande, Tsesmetzis, Nikolaos, Sharma, Sushma, Hofmann, Sophia, Thier, Jonas, Dirks, Christopher, Hormann, Femke M., Yagüe Capilla, Miriam, Herold, Nikolas
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2025
País:España
Institución:Universidad de Sevilla (US)
Repositorio:idUS. Depósito de Investigación de la Universidad de Sevilla
OAI Identifier:oai:idus.us.es:11441/182100
Acceso en línea:https://hdl.handle.net/11441/182100
https://doi.org/10.1080/15384101.2025.2601796
Access Level:acceso abierto
Palabra clave:IMPDH
KMT2A
Leukemia
SAMHD1
Therapy resistance
id ES_cde88f6bdb63704c21ac54ff643da7ea
oai_identifier_str oai:idus.us.es:11441/182100
network_acronym_str ES
network_name_str España
repository_id_str
spelling Targeting IMPDH to inhibit SAMHD1 in KMT2A-rearranged leukaemiaKlootsema, YolandeTsesmetzis, NikolaosSharma, SushmaHofmann, SophiaThier, JonasDirks, ChristopherHormann, Femke M.Yagüe Capilla, MiriamHerold, NikolasIMPDHKMT2ALeukemiaSAMHD1Therapy resistanceCytarabine (ara-C) and fludarabine (F-ara-A) are key drugs in leukaemia treatment. SAMHD1 is known to confer resistance to ara-C and F-ara-A, and we previously identified ribonucleotide reductase inhibitors as indirect SAMHD1 inhibitors in a phenotypic screen. The inosine monophosphate dehydrogenase (IMPDH) inhibitor mycophenolic acid (MPA) was also a hit in this screen. IMPDH inhibitors (IMPDHi) have previously shown efficacy against KMT2A-rearranged (KMT2Ar) acute myeloid leukaemia (AML). We investigated whether IMPDH inhibition could enhance the effect of ara-C and F-ara-A in AML cell lines and primary AML samples, and whether this effect was linked to KMT2A status. We found that sensitivity to IMPDHi was independent of KMT2A status. IMPDHi synergized with ara-C and F-ara-A in a SAMHD1-dependent manner in a subset of AML cells, but not in acute lymphoblastic leukaemia cell lines. Mechanistically, IMPDHi depleted allosteric SAMHD1 activators GTP and dGTP, thereby increasing active triphosphate metabolites in SAMHD1-proficient, but not SAMHD1-deficient, cells. Our findings suggest that the addition of IMPDHi to ara-C and F-ara-A may have therapeutic benefits in some AML cases.Taylor & Francis Inc.Biología CelularSwedish Society for Medical ResearchSwedish Cancer SocietySwedish Childhood Cancer FoundationSwedish Society of MedicineSjöberg FoundationSwedish Research Council2025info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttps://hdl.handle.net/11441/182100https://doi.org/10.1080/15384101.2025.2601796reponame:idUS. Depósito de Investigación de la Universidad de Sevillainstname:Universidad de Sevilla (US)InglésCell Cycle.SG-23–0178-B24–0829-PT19–0056-JIA23–2782-Pj24 3398 Pj25 3999 IA JCIA22–2377-PTJ2022-0063PR2022-0003PR2023-0031SLS-998532020–0082024–029412022–006752020–01902https://doi.org/10.1080/15384101.2025.2601796info:eu-repo/semantics/openAccessoai:idus.us.es:11441/1821002026-06-17T12:51:07Z
dc.title.none.fl_str_mv Targeting IMPDH to inhibit SAMHD1 in KMT2A-rearranged leukaemia
title Targeting IMPDH to inhibit SAMHD1 in KMT2A-rearranged leukaemia
spellingShingle Targeting IMPDH to inhibit SAMHD1 in KMT2A-rearranged leukaemia
Klootsema, Yolande
IMPDH
KMT2A
Leukemia
SAMHD1
Therapy resistance
title_short Targeting IMPDH to inhibit SAMHD1 in KMT2A-rearranged leukaemia
title_full Targeting IMPDH to inhibit SAMHD1 in KMT2A-rearranged leukaemia
title_fullStr Targeting IMPDH to inhibit SAMHD1 in KMT2A-rearranged leukaemia
title_full_unstemmed Targeting IMPDH to inhibit SAMHD1 in KMT2A-rearranged leukaemia
title_sort Targeting IMPDH to inhibit SAMHD1 in KMT2A-rearranged leukaemia
dc.creator.none.fl_str_mv Klootsema, Yolande
Tsesmetzis, Nikolaos
Sharma, Sushma
Hofmann, Sophia
Thier, Jonas
Dirks, Christopher
Hormann, Femke M.
Yagüe Capilla, Miriam
Herold, Nikolas
author Klootsema, Yolande
author_facet Klootsema, Yolande
Tsesmetzis, Nikolaos
Sharma, Sushma
Hofmann, Sophia
Thier, Jonas
Dirks, Christopher
Hormann, Femke M.
Yagüe Capilla, Miriam
Herold, Nikolas
author_role author
author2 Tsesmetzis, Nikolaos
Sharma, Sushma
Hofmann, Sophia
Thier, Jonas
Dirks, Christopher
Hormann, Femke M.
Yagüe Capilla, Miriam
Herold, Nikolas
author2_role author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Biología Celular
Swedish Society for Medical Research
Swedish Cancer Society
Swedish Childhood Cancer Foundation
Swedish Society of Medicine
Sjöberg Foundation
Swedish Research Council
dc.subject.none.fl_str_mv IMPDH
KMT2A
Leukemia
SAMHD1
Therapy resistance
topic IMPDH
KMT2A
Leukemia
SAMHD1
Therapy resistance
description Cytarabine (ara-C) and fludarabine (F-ara-A) are key drugs in leukaemia treatment. SAMHD1 is known to confer resistance to ara-C and F-ara-A, and we previously identified ribonucleotide reductase inhibitors as indirect SAMHD1 inhibitors in a phenotypic screen. The inosine monophosphate dehydrogenase (IMPDH) inhibitor mycophenolic acid (MPA) was also a hit in this screen. IMPDH inhibitors (IMPDHi) have previously shown efficacy against KMT2A-rearranged (KMT2Ar) acute myeloid leukaemia (AML). We investigated whether IMPDH inhibition could enhance the effect of ara-C and F-ara-A in AML cell lines and primary AML samples, and whether this effect was linked to KMT2A status. We found that sensitivity to IMPDHi was independent of KMT2A status. IMPDHi synergized with ara-C and F-ara-A in a SAMHD1-dependent manner in a subset of AML cells, but not in acute lymphoblastic leukaemia cell lines. Mechanistically, IMPDHi depleted allosteric SAMHD1 activators GTP and dGTP, thereby increasing active triphosphate metabolites in SAMHD1-proficient, but not SAMHD1-deficient, cells. Our findings suggest that the addition of IMPDHi to ara-C and F-ara-A may have therapeutic benefits in some AML cases.
publishDate 2025
dc.date.none.fl_str_mv 2025
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/11441/182100
https://doi.org/10.1080/15384101.2025.2601796
url https://hdl.handle.net/11441/182100
https://doi.org/10.1080/15384101.2025.2601796
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Cell Cycle.
SG-23–0178-B
24–0829-PT
19–0056-JIA
23–2782-Pj
24 3398 Pj
25 3999 IA JCIA
22–2377-P
TJ2022-0063
PR2022-0003
PR2023-0031
SLS-99853
2020–008
2024–02941
2022–00675
2020–01902
https://doi.org/10.1080/15384101.2025.2601796
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Taylor & Francis Inc.
publisher.none.fl_str_mv Taylor & Francis Inc.
dc.source.none.fl_str_mv reponame:idUS. Depósito de Investigación de la Universidad de Sevilla
instname:Universidad de Sevilla (US)
instname_str Universidad de Sevilla (US)
reponame_str idUS. Depósito de Investigación de la Universidad de Sevilla
collection idUS. Depósito de Investigación de la Universidad de Sevilla
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869419898012172288
score 15,812455

Similares en LA Referencia