MDMX acts as a pervasive preleukemic-to-acute myeloid leukemia transition mechanism.
CK1α
MDMX
acute myeloid leukemia
cancer interception
myelodysplastic syndromes
precision prevention
preleukemia
preleukemic stem cells
targeted therapy
β-Catenin
Journal
Cancer cell
ISSN: 1878-3686
Titre abrégé: Cancer Cell
Pays: United States
ID NLM: 101130617
Informations de publication
Date de publication:
12 04 2021
12 04 2021
Historique:
received:
12
05
2020
revised:
23
11
2020
accepted:
08
02
2021
pubmed:
6
3
2021
medline:
17
11
2021
entrez:
5
3
2021
Statut:
ppublish
Résumé
MDMX is overexpressed in the vast majority of patients with acute myeloid leukemia (AML). We report that MDMX overexpression increases preleukemic stem cell (pre-LSC) number and competitive advantage. Utilizing five newly generated murine models, we found that MDMX overexpression triggers progression of multiple chronic/asymptomatic preleukemic conditions to overt AML. Transcriptomic and proteomic studies revealed that MDMX overexpression exerts this function, unexpectedly, through activation of Wnt/β-Catenin signaling in pre-LSCs. Mechanistically, MDMX binds CK1α and leads to accumulation of β-Catenin in a p53-independent manner. Wnt/β-Catenin inhibitors reverse MDMX-induced pre-LSC properties, and synergize with MDMX-p53 inhibitors. Wnt/β-Catenin signaling correlates with MDMX expression in patients with preleukemic myelodysplastic syndromes and is associated with increased risk of progression to AML. Our work identifies MDMX overexpression as a pervasive preleukemic-to-AML transition mechanism in different genetically driven disease subtypes, and reveals Wnt/β-Catenin as a non-canonical MDMX-driven pathway with therapeutic potential for progression prevention and cancer interception.
Identifiants
pubmed: 33667384
pii: S1535-6108(21)00108-2
doi: 10.1016/j.ccell.2021.02.006
pmc: PMC8575661
mid: NIHMS1683060
pii:
doi:
Substances chimiques
CTNNB1 protein, human
0
Cell Cycle Proteins
0
MDM4 protein, human
0
Mdm4 protein, mouse
0
Proto-Oncogene Proteins
0
beta Catenin
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
529-547.e7Subventions
Organisme : NHLBI NIH HHS
ID : R01 HL139487
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA217092
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA047296
Pays : United States
Organisme : NIGMS NIH HHS
ID : F30 GM122308
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM007288
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA013330
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL150832
Pays : United States
Informations de copyright
Copyright © 2021 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests L.A.C. is a past employee of Aileron Therapeutics. J.C. is currently an employee of Stelexis Therapeutics. ALRN-6924 was provided to U.S. from Aileron Therapeutics. U.S. has received research funding from GlaxoSmithKline, Bayer HealthCare, Aileron Therapeutics, and Novartis; has received compensation for consultancy services and for serving on scientific advisory boards from GlaxoSmithKline, Bayer Healthcare, Celgene, Aileron Therapeutics, Stelexis Therapeutics, and Pieris Pharmaceuticals; and has equity ownership in and is serving on the board of directors of Stelexis Therapeutics.
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