Loss of the stress sensor GADD45A promotes stem cell activity and ferroptosis resistance in LGR4/HOXA9-dependent AML

被引：6

作者：

Hassan, Nunki ^{[1
]}

Yi, Hangyu ^{[1
]}

Malik, Bilal ^{[1
]}

Gaspard-Boulinc, Lucie ^{[1
,2
]}

Samaraweera, Saumya E. ^{[3
]}

Casolari, Debora A. ^{[3
]}

Seneviratne, Janith ^{[4
]}

Balachandran, Anushree ^{[4
]}

Chew, Tracy ^{[5
]}

Duly, Alastair ^{[4
]}

Carter, Daniel R. ^{[4
]}

Cheung, Belamy B. ^{[4
]}

Norris, Murray ^{[4
]}

Haber, Michelle ^{[4
]}

Kavallaris, Maria ^{[4
,6
,7
]}

Marshall, Glenn M. ^{[4
,8
]}

Zhang, Xu Dong ^{[9
,10
,11
]}

Liu, Tao ^{[4
]}

Wang, Jianlong ^{[12
]}

Liebermann, Dan A. ^{[13
,14
]}

'Andrea, Richard J. D. ^{[3
]}

Wang, Jenny Y. ^{[1
]}

机构：

[1] Univ Sydney, Kolling Inst, Fac Med & Hlth, Sch Med Sci,Canc & Stem Cell Lab, Sydney, NSW, Australia

[2] PSL Univ Paris, Ecole Normale Super, Dept Biol, Paris, France

[3] Univ South Australia & SA Pathol, Ctr Canc Biol, Acute Leukaemia Lab, Adelaide, SA, Australia

[4] Univ New South Wales, Childrens Canc Inst, Lowy Canc Res Ctr, Sydney, NSW, Australia

[5] Univ Sydney, Sydney Informat Hub, Core Res Facil, Camperdown, NSW, Australia

[6] Univ New South Wales, Australian Ctr Nanomed, Sydney, NSW, Australia

[7] Univ New South Wales, ARC Ctr Excellence Convergent Bionano Sci & Techno, Sydney, NSW, Australia

[8] Sydney Childrens Hosp, Kids Canc Ctr, Randwick, NSW, Australia

[9] Univ Newcastle, Sch Biomed Sci & Pharm, Callaghan, NSW, Australia

[10] Peoples Hosp Zhengzhou Univ, Zhengzhou Univ, Henan Prov Peoples Hosp, Translat Res Inst, Zhengzhou, Henan, Peoples R China

[11] Zhengzhou Univ, Peoples Hosp, Acad Med Sci, Zhengzhou, Henan, Peoples R China

[12] Columbia Univ, Columbia Ctr Human Dev, Dept Med, Irving Med Ctr, New York, NY USA

[13] Temple Univ, Fels Inst Canc Res & Mol Biol, Sch Med, Philadelphia, PA USA

[14] Temple Univ, Sch Med, Dept Med Genet & Mol Biochem, Philadelphia, PA USA

来源：

BLOOD | 2024年 / 144卷 / 01期

关键词：

ACUTE MYELOID-LEUKEMIA; BETA-CATENIN; DNA-DAMAGE; EXPRESSION; POOR; PHOSPHORYLATION; DIFFERENTIATION; MAINTENANCE; APOPTOSIS; SURVIVAL;

D O I：

10.1182/blood.2024024072

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

The overall prognosis of acute myeloid leukemia (AML) remains dismal, largely because of the inability of current therapies to kill leukemia stem cells (LSCs) with intrinsic resistance. Loss of the stress sensor growth arrest and DNA damage-inducible 45 alpha (GADD45A) is implicated in poor clinical outcomes, but its role in LSCs and AML pathogenesis is unknown. Here, we define GADD45A as a key downstream target of G protein-coupled receptor (LGR)4 pathway and discover a regulatory role for GADD45A loss in promoting leukemia-initiating activity and oxidative resistance in LGR4/HOXA9-dependent AML, a poor prognosis subset of leukemia. Knockout of GADD45A enhances AML progression in murine and patient-derived xenograft (PDX) mouse models. Deletion of GADD45A induces substantial mutations, increases LSC self-renewal and stemness in vivo, and reduces levels of reactive oxygen species (ROS), accompanied by a decreased response to ROS-associated genotoxic agents (eg, ferroptosis inducer RSL3) and acquisition of an increasingly aggressive phenotype on serial transplantation in mice. Our single-cell cellular indexing of transcriptomes and epitopes by sequencing analysis on patient-derived LSCs in PDX mice and subsequent functional studies in murine LSCs and primary AML patient cells show that loss of GADD45A is associated with resistance to ferroptosis (an iron-dependent oxidative cell death caused by ROS accumulation) through aberrant activation of antioxidant pathways related to iron and ROS detoxification, such as FTH1 and PRDX1, upregulation of which correlates with unfavorable outcomes in patients with AML. These results reveal a therapy resistance mechanism contributing to poor prognosis and support a role for GADD45A loss as a critical step for leukemia-initiating activity and as a target to overcome resistance in aggressive leukemia.

引用

页码：84 / 98

页数：15