MDMX acts as a pervasive preleukemic-to-acute myeloid leukemia transition mechanism

Koki Ueda; Rajni Kumari; Emily Schwenger; Justin C. Wheat; Oliver Bohorquez; Swathi Rao Narayanagari; Samuel J. Taylor; Luis A. Carvajal; Kith Pradhan; Boris Bartholdy; Tihomira I. Todorova; Hiroki Goto; Daqian Sun; Jiahao Chen; Jidong Shan; Yinghui Song; Cristina Montagna; Shunbin Xiong; Guillermina Lozano; Andrea Pellagatti; Jacqueline Boultwood; Amit Verma; Ulrich Steidl

doi:10.1016/j.ccell.2021.02.006

MDMX acts as a pervasive preleukemic-to-acute myeloid leukemia transition mechanism

Koki Ueda, Rajni Kumari, Emily Schwenger, Justin C. Wheat, Oliver Bohorquez, Swathi Rao Narayanagari, Samuel J. Taylor, Luis A. Carvajal, Kith Pradhan, Boris Bartholdy, Tihomira I. Todorova, Hiroki Goto, Daqian Sun, Jiahao Chen, Jidong Shan, Yinghui Song, Cristina Montagna, Shunbin Xiong, Guillermina Lozano, Andrea PellagattiJacqueline Boultwood, Amit Verma, Ulrich Steidl

Research output: Contribution to journal › Article › peer-review

18 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	529-547.e7
Journal	Cancer Cell
Volume	39
Issue number	4
DOIs	https://doi.org/10.1016/j.ccell.2021.02.006
State	Published - Apr 12 2021

Keywords

CK1α
MDMX
acute myeloid leukemia
cancer interception
myelodysplastic syndromes
precision prevention
preleukemia
preleukemic stem cells
targeted therapy
β-Catenin

ASJC Scopus subject areas

Oncology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.ccell.2021.02.006

Cite this

Ueda, K., Kumari, R., Schwenger, E., Wheat, J. C., Bohorquez, O., Narayanagari, S. R., Taylor, S. J., Carvajal, L. A., Pradhan, K., Bartholdy, B., Todorova, T. I., Goto, H., Sun, D., Chen, J., Shan, J., Song, Y., Montagna, C., Xiong, S., Lozano, G., ... Steidl, U. (2021). MDMX acts as a pervasive preleukemic-to-acute myeloid leukemia transition mechanism. Cancer Cell, 39(4), 529-547.e7. https://doi.org/10.1016/j.ccell.2021.02.006

Ueda, K, Kumari, R, Schwenger, E, Wheat, JC, Bohorquez, O, Narayanagari, SR , Taylor, SJ, Carvajal, LA, Pradhan, K, Bartholdy, B, Todorova, TI, Goto, H, Sun, D, Chen, J, Shan, J, Song, Y, Montagna, C, Xiong, S, Lozano, G, Pellagatti, A, Boultwood, J, Verma, A & Steidl, U 2021, 'MDMX acts as a pervasive preleukemic-to-acute myeloid leukemia transition mechanism', Cancer Cell, vol. 39, no. 4, pp. 529-547.e7. https://doi.org/10.1016/j.ccell.2021.02.006

@article{b5e0c64764ec4560b4564a8122b368ea,

title = "MDMX acts as a pervasive preleukemic-to-acute myeloid leukemia transition mechanism",

abstract = "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.",

keywords = "CK1α, MDMX, acute myeloid leukemia, cancer interception, myelodysplastic syndromes, precision prevention, preleukemia, preleukemic stem cells, targeted therapy, β-Catenin",

author = "Koki Ueda and Rajni Kumari and Emily Schwenger and Wheat, {Justin C.} and Oliver Bohorquez and Narayanagari, {Swathi Rao} and Taylor, {Samuel J.} and Carvajal, {Luis A.} and Kith Pradhan and Boris Bartholdy and Todorova, {Tihomira I.} and Hiroki Goto and Daqian Sun and Jiahao Chen and Jidong Shan and Yinghui Song and Cristina Montagna and Shunbin Xiong and Guillermina Lozano and Andrea Pellagatti and Jacqueline Boultwood and Amit Verma and Ulrich Steidl",

note = "Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",

year = "2021",

month = apr,

day = "12",

doi = "10.1016/j.ccell.2021.02.006",

language = "English (US)",

volume = "39",

pages = "529--547.e7",

journal = "Cancer Cell",

issn = "1535-6108",

publisher = "Cell Press",

number = "4",

}

TY - JOUR

T1 - MDMX acts as a pervasive preleukemic-to-acute myeloid leukemia transition mechanism

AU - Ueda, Koki

AU - Kumari, Rajni

AU - Schwenger, Emily

AU - Wheat, Justin C.

AU - Bohorquez, Oliver

AU - Narayanagari, Swathi Rao

AU - Taylor, Samuel J.

AU - Carvajal, Luis A.

AU - Pradhan, Kith

AU - Bartholdy, Boris

AU - Todorova, Tihomira I.

AU - Goto, Hiroki

AU - Sun, Daqian

AU - Chen, Jiahao

AU - Shan, Jidong

AU - Song, Yinghui

AU - Montagna, Cristina

AU - Xiong, Shunbin

AU - Lozano, Guillermina

AU - Pellagatti, Andrea

AU - Boultwood, Jacqueline

AU - Verma, Amit

AU - Steidl, Ulrich

PY - 2021/4/12

Y1 - 2021/4/12

N2 - 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.

AB - 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.

KW - CK1α

KW - MDMX

KW - acute myeloid leukemia

KW - cancer interception

KW - myelodysplastic syndromes

KW - precision prevention

KW - preleukemia

KW - preleukemic stem cells

KW - targeted therapy

KW - β-Catenin

UR - http://www.scopus.com/inward/record.url?scp=85103034443&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85103034443&partnerID=8YFLogxK

U2 - 10.1016/j.ccell.2021.02.006

DO - 10.1016/j.ccell.2021.02.006

M3 - Article

C2 - 33667384

AN - SCOPUS:85103034443

SN - 1535-6108

VL - 39

SP - 529-547.e7

JO - Cancer Cell

JF - Cancer Cell

IS - 4

ER -

MDMX acts as a pervasive preleukemic-to-acute myeloid leukemia transition mechanism

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this