Evidence map›Paper›PMID 38579286›Full record

ArticleBlood2024

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

Nunki Hassan, Hangyu Yi, Bilal Malik, Lucie Gaspard-Boulinc, Saumya E Samaraweera, Debora A Casolari, Janith Seneviratne, Anushree Balachandran, Tracy Chew, Alastair Duly and 12 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Blood, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.

0numbers the graph read from it
0cells of the map it votes in
20citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

20 citing papers in PubMed.

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4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

22 authors.

Nunki HassanCancer and Stem Cell Laboratory, School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Kolling Institute, Sydney, NSW, Australia.ORCID 0000-0003-0978-0376
Hangyu YiCancer and Stem Cell Laboratory, School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Kolling Institute, Sydney, NSW, Australia.
Bilal MalikCancer and Stem Cell Laboratory, School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Kolling Institute, Sydney, NSW, Australia.ORCID 0000-0002-9543-7875
Lucie Gaspard-BoulincCancer and Stem Cell Laboratory, School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Kolling Institute, Sydney, NSW, Australia.ORCID 0000-0002-0782-9511
Saumya E SamaraweeraAcute Leukaemia Laboratory, Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA, Australia.ORCID 0000-0002-9619-0624
Debora A CasolariAcute Leukaemia Laboratory, Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA, Australia.
Janith SeneviratneChildren's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia.ORCID 0000-0003-0413-5829
Anushree BalachandranChildren's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia.
Tracy ChewSydney Informatics Hub, Core Research Facilities, University of Sydney, Camperdown, NSW, Australia.ORCID 0000-0001-9529-7705
Alastair DulyChildren's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia.ORCID 0000-0001-6843-1956
Daniel R CarterChildren's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia.
Belamy B CheungChildren's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia.ORCID 0000-0001-8784-860X
Murray NorrisChildren's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia.ORCID 0000-0002-0632-4589
Michelle HaberChildren's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia.ORCID 0000-0003-2036-8817
Maria KavallarisChildren's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia.
Glenn M MarshallChildren's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia.
Xu Dong ZhangSchool of Biomedical Sciences and Pharmacy, The University of Newcastle, Callaghan, NSW, Australia.
Tao LiuChildren's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia.
Jianlong WangDepartment of Medicine, Columbia Center for Human Development, Columbia University Irving Medical Center, New York, NY.
Dan A LiebermannFels Institute for Cancer Research and Molecular Biology and Department of Medical Genetics and Molecular Biochemistry, School of Medicine, Temple University, Philadelphia, PA.
Richard J D'AndreaAcute Leukaemia Laboratory, Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA, Australia.ORCID 0000-0002-4915-4612
Jenny Y WangCancer and Stem Cell Laboratory, School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Kolling Institute, Sydney, NSW, Australia.ORCID 0000-0002-1325-7943

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

abstractThe 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.

Indexed as

Cell Cycle ProteinsFerroptosisLeukemia, Myeloid, AcuteNeoplastic Stem CellsAnimalsGADD45 ProteinsHumansMiceMice, KnockoutReceptors, G-Protein-CoupledCell Cycle ProteinsGADD45A protein, humanGadd45a protein, mouseGADD45 ProteinsReceptors, G-Protein-Coupled

Identifiers

PMID38579286
PMCPMC11251412

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LicenceCC BY-NC-ND
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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.