Targeting Acute Myeloid Leukemia Stem Cells through Perturbation of Mitochondrial Calcium

被引：0

作者：

Sheth, Anagha Inguva ^{[1
]}

Althoff, Mark J. ^{[1
]}

Tolison, Hunter ^{[1
]}

Engel, Krysta ^{[1
]}

Amaya, Maria L. ^{[1
]}

Krug, Anna E. ^{[1
]}

Young, Tracy N. ^{[1
]}

Minhajuddin, Mohammad ^{[1
]}

Pei, Shanshan ^{[2
,3
]}

Patel, Sweta B. ^{[1
]}

Winters, Amanda ^{[4
]}

Miller, Regan ^{[1
]}

Shelton, Ian T. ^{[1
]}

St-Germain, Jonathan ^{[5
,6
]}

Ling, Tianyi ^{[5
,6
]}

Jones, Courtney L. ^{[7
]}

Raught, Brian ^{[5
,6
]}

Gillen, Austin E. ^{[1
]}

Ransom, Monica ^{[1
]}

Staggs, Sarah ^{[1
]}

Smith, Clayton A. ^{[1
]}

Pollyea, Daniel A. ^{[1
]}

Stevens, Brett M. ^{[1
]}

Jordan, Craig T. ^{[1
]}

机构：

[1] Univ Colorado, Sch Med, Div Hematol, Aurora, CO 80045 USA

[2] Zhejiang Univ, Sch Med, Bone Marrow Transplantat Ctr, Affiliated Hosp 1, Hangzhou, Peoples R China

[3] Zhejiang Univ, Sch Med, Liangzhu Lab, Hangzhou, Peoples R China

[4] Univ Colorado, Sch Med, Div Pediat Hematol & Oncol, Aurora, CO 80045 USA

[5] Univ Hlth Network, Princess Margaret Canc Ctr, Toronto, ON, Canada

[6] Univ Toronto, Dept Med Biophys, Toronto, ON, Canada

[7] Cincinnati Childrens Hosp Med Ctr, Div Expt Hematol & Canc Biol, Cincinnati, OH USA

来源：

CANCER DISCOVERY | 2024年 / 14卷 / 10期

关键词：

SARCOPLASMIC/ENDOPLASMIC RETICULUM CA2+-ATPASE; ALPHA-KETOGLUTARATE DEHYDROGENASE; DEPENDENT ANION CHANNEL; ENDOPLASMIC-RETICULUM; BH4; DOMAIN; BCL-2; VENETOCLAX; INHIBITION; METABOLISM; RESISTANCE;

D O I：

暂无

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Analysis of therapy-resistant leukemia stem cells (LSC) revealed that inhibition of mitochondrial calcium uptake acts to inhibit oxidative phosphorylation, thereby leading to subsequent eradication of LSCs. Acute myeloid leukemia stem cells (LSCs) are uniquely reliant on oxidative phosphorylation (OXPHOS) for survival. Moreover, maintenance of OXPHOS is dependent on BCL-2, creating a therapeutic opportunity to target LSCs using the BCL-2 inhibitor venetoclax. Although venetoclax-based regimens have shown promising clinical activity, the emergence of drug resistance is prevalent. Thus, in the present study, we investigated how mitochondrial properties may influence venetoclax responsiveness. Our data show that utilization of mitochondrial calcium is fundamentally different between drug-responsive and nonresponsive LSCs. By comparison, venetoclax-resistant LSCs demonstrate an active metabolic (i.e., OXPHOS) status with relatively high levels of calcium. Consequently, we tested genetic and pharmacological approaches to target the mitochondrial calcium uniporter. We demonstrate that inhibition of calcium uptake reduces OXPHOS and leads to eradication of venetoclax-resistant LSCs. These findings demonstrate a central role for calcium signaling in LSCs and provide an avenue for clinical management of venetoclax resistance.Significance: We identify increased utilization of mitochondrial calcium as a distinct metabolic requirement of venetoclax-resistant LSCs and demonstrate the potential of targeting mitochondrial calcium uptake as a therapeutic strategy.

引用

页码：1922 / 1939

页数：18

共 60 条

[41] Targeting Bcl-2-IP3 receptor interaction to reverse Bcl-2's inhibition of apoptotic calcium signals [J].

Rong, Yi-Ping ;

Aromolaran, Ademuyiwa S. ;

Bultynck, Geert ;

Zhong, Fei ;

Li, Xiang ;

McColl, Karen ;

Matsuyama, Shigemi ;

Herlitze, Stephan ;

Roderick, H. Llewelyn ;

Bootman, Martin D. ;

Mignery, Gregory A. ;

Parys, Jan B. ;

De Smedt, Humbert ;

Distelhorst, Clark W. .

MOLECULAR CELL, 2008, 31 (02) :255-265

[42] The BH4 domain of Bcl-2 inhibits ER calcium release and apoptosis by binding the regulatory and coupling domain of the IP3 receptor [J].

Rong, Yi-Ping ;

Bultynck, Geert ;

Aromolaran, Ademuyiwa S. ;

Zhong, Fei ;

Parys, Jan B. ;

De Smedt, Humbert ;

Mignery, Gregory A. ;

Roderickd, H. Llewelyn ;

Bootman, Martin D. ;

Distelhorst, Clark W. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2009, 106 (34) :14397-14402

[43] Complementary Genomic Screens Identify SERCA as a Therapeutic Target in NOTCH1 Mutated Cancer [J].

Roti, Giovanni ;

Carlton, Anne ;

Ross, Kenneth N. ;

Markstein, Michele ;

Pajcini, Kostandin ;

Su, Angela H. ;

Perrimon, Norbert ;

Pear, Warren S. ;

Kung, Andrew L. ;

Blacklow, Stephen C. ;

Aster, Jon C. ;

Stegmaier, Kimberly .

CANCER CELL, 2013, 23 (03) :390-405

[44] Mitochondrial calcium overload is a key determinant in heart failure [J].

Santulli, Gaetano ;

Xie, Wenjun ;

Reiken, Steven R. ;

Marks, Andrew R. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2015, 112 (36) :11389-11394

[45] Minocycline and doxycycline, but not other tetracycline-derived compounds, protect liver cells from chemical hypoxia and ischemia/reperfusion injury by inhibition of the mitochondrial calcium uniporter [J].

Schwartz, Justin ;

Holmuhamedov, Ekhson ;

Zhang, Xun ;

Lovelace, Gregory L. ;

Smith, Charles D. ;

Lemasters, John J. .

TOXICOLOGY AND APPLIED PHARMACOLOGY, 2013, 273 (01) :172-179

[46] BH4 domain of antiapoptotic Bcl-2 family members closes voltage-dependent anion channel and inhibits apoptotic mitochondrial changes and cell death [J].

Shimizu, S ;

Konishi, A ;

Kodama, T ;

Tsujimoto, Y .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2000, 97 (07) :3100-3105

[47] Fatty acid metabolism underlies venetoclax resistance in acute myeloid leukemia stem cells [J].

Stevens, Brett M. ;

Jones, Courtney L. ;

Pollyea, Daniel A. ;

Culp-Hill, Rachel ;

D'Alessandro, Angelo ;

Winters, Amanda ;

Krug, Anna ;

Abbott, Diana ;

Goosman, Madeline ;

Pei, Shanshan ;

Ye, Haobin ;

Gillen, Austin E. ;

Becker, Michael W. ;

Savona, Michael R. ;

Smith, Clayton ;

Jordan, Craig T. .

NATURE CANCER, 2020, 1 (12) :1176-+

[48] Enriching for human acute myeloid leukemia stem cells using reactive oxygen species-based cell sorting [J].

Stevens, Brett M. ;

O'Brien, Cristiana ;

Jordan, Craig T. ;

Jones, Courtney L. .

STAR PROTOCOLS, 2021, 2 (01)

[49] Role of the calcium toolkit in cancer stem cells [J].

Terrie, Elodie ;

Coronas, Valerie ;

Constantin, Bruno .

CELL CALCIUM, 2019, 80 :141-151

[50] Role of calcium signaling in the activation of mitochondrial nitric oxide synthase and citric acid cycle [J].

Traaseth, N ;

Elfering, S ;

Solien, J ;

Haynes, V ;

Giulivi, C .

BIOCHIMICA ET BIOPHYSICA ACTA-BIOENERGETICS, 2004, 1658 (1-2) :64-71

← 1 2 3 4 5 6 →