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

Hassan, N; Yi, H; Malik, B; Gaspard-Boulinc, L; Samaraweera, SE; Casolari, DA; Seneviratne, J; Balachandran, A; Chew, T; Duly, A; Carter, DR; Cheung, BB; Norris, M; Haber, M; Kavallaris, M; Marshall, GM; Zhang, XD; Liu, T; Wang, J; Liebermann, DA; D'Andrea, RJ; Wang, JY

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

Hassan, N Yi, H Malik, B Gaspard-Boulinc, L Samaraweera, SE Casolari, DA Seneviratne, J Balachandran, A Chew, T Duly, A Carter, DR Cheung, BB Norris, M Haber, M Kavallaris, M Marshall, GM Zhang, XD Liu, T Wang, J Liebermann, DA D'Andrea, RJ Wang, JY

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Publisher:: American Society of Hematology
Publication Type:: Journal Article
Citation:: Blood, 2024, 144, (1), pp. 84-98
Issue Date:: 2024-07-04

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Field	Value	Language
dc.contributor.author	Hassan, N
dc.contributor.author	Yi, H
dc.contributor.author	Malik, B
dc.contributor.author	Gaspard-Boulinc, L
dc.contributor.author	Samaraweera, SE
dc.contributor.author	Casolari, DA
dc.contributor.author	Seneviratne, J
dc.contributor.author	Balachandran, A
dc.contributor.author	Chew, T
dc.contributor.author	Duly, A
dc.contributor.author	Carter, DR
dc.contributor.author	Cheung, BB
dc.contributor.author	Norris, M
dc.contributor.author	Haber, M
dc.contributor.author	Kavallaris, M
dc.contributor.author	Marshall, GM
dc.contributor.author	Zhang, XD
dc.contributor.author	Liu, T
dc.contributor.author	Wang, J
dc.contributor.author	Liebermann, DA
dc.contributor.author	D'Andrea, RJ
dc.contributor.author	Wang, JY
dc.date.accessioned	2025-04-03T06:19:53Z
dc.date.available	2024-03-15
dc.date.available	2025-04-03T06:19:53Z
dc.date.issued	2024-07-04
dc.identifier.citation	Blood, 2024, 144, (1), pp. 84-98
dc.identifier.issn	0006-4971
dc.identifier.issn	1528-0020
dc.identifier.uri	http://hdl.handle.net/10453/186564
dc.description.abstract	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.
dc.format	Print
dc.language	eng
dc.publisher	American Society of Hematology
dc.relation.ispartof	Blood
dc.relation.isbasedon	10.1182/blood.2024024072
dc.rights	info:eu-repo/semantics/closedAccess
dc.subject	1102 Cardiorespiratory Medicine and Haematology, 1103 Clinical Sciences, 1114 Paediatrics and Reproductive Medicine
dc.subject.classification	Immunology
dc.subject.classification	3101 Biochemistry and cell biology
dc.subject.classification	3201 Cardiovascular medicine and haematology
dc.subject.classification	3213 Paediatrics
dc.subject.mesh	Animals
dc.subject.mesh	Leukemia, Myeloid, Acute
dc.subject.mesh	Mice
dc.subject.mesh	Humans
dc.subject.mesh	Ferroptosis
dc.subject.mesh	Neoplastic Stem Cells
dc.subject.mesh	Cell Cycle Proteins
dc.subject.mesh	Mice, Knockout
dc.subject.mesh	Receptors, G-Protein-Coupled
dc.subject.mesh	GADD45 Proteins
dc.subject.mesh	Animals
dc.subject.mesh	Mice, Knockout
dc.subject.mesh	Humans
dc.subject.mesh	Mice
dc.subject.mesh	Cell Cycle Proteins
dc.subject.mesh	Receptors, G-Protein-Coupled
dc.subject.mesh	Neoplastic Stem Cells
dc.subject.mesh	Leukemia, Myeloid, Acute
dc.subject.mesh	Ferroptosis
dc.subject.mesh	GADD45 Proteins
dc.subject.mesh	Animals
dc.subject.mesh	Leukemia, Myeloid, Acute
dc.subject.mesh	Mice
dc.subject.mesh	Humans
dc.subject.mesh	Ferroptosis
dc.subject.mesh	Neoplastic Stem Cells
dc.subject.mesh	Cell Cycle Proteins
dc.subject.mesh	Mice, Knockout
dc.subject.mesh	Receptors, G-Protein-Coupled
dc.subject.mesh	GADD45 Proteins
dc.title	Loss of the stress sensor GADD45A promotes stem cell activity and ferroptosis resistance in LGR4/HOXA9-dependent AML.
dc.type	Journal Article
utslib.citation.volume	144
utslib.location.activity	United States
utslib.for	1102 Cardiorespiratory Medicine and Haematology
utslib.for	1103 Clinical Sciences
utslib.for	1114 Paediatrics and Reproductive Medicine
pubs.organisational-group	University of Technology Sydney
pubs.organisational-group	University of Technology Sydney/Faculty of Engineering and Information Technology
pubs.organisational-group	University of Technology Sydney/Faculty of Engineering and Information Technology/School of Biomedical Engineering
pubs.organisational-group	University of Technology Sydney/UTS Groups
pubs.organisational-group	University of Technology Sydney/UTS Groups/Centre for Health Technologies (CHT)
utslib.copyright.status	closed_access	*
dc.date.updated	2025-04-03T06:19:52Z
pubs.issue	1
pubs.publication-status	Published
pubs.volume	144
utslib.citation.issue	1

Abstract:

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.

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http://hdl.handle.net/10453/186564