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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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GADD45A loss enhances leukemia-initiating cell self-renewal and ferroptosis resistance in AML

ABSTRACT: Loss of GADD45A expression is implicated in poor patient outcomes in acute myeloid leukemia (AML) but its role in leukemia stem cells (LSCs) and disease pathogenesis remains largely unknown. Here we report that GADD45A loss is a critical determinant of high self-renewal potential and knockout of GADD45A supports long-term self-renewal and promotes LSC quiescence, accompanied by the acquisition of an increasingly aggressive phenotype upon serial transplantation in mice. The enhanced LSC characteristics are associated with GADD45A deletion-induced increase in key WNT/self-renewal-related genes. GADD45A knockout promotes engraftment of patient-derived xenograft (PDX) of relapsed AML in mice. Single cell RNA-seq on primary LSCs of AML PDXs and subsequent functional studies show that low expression of GADD45A, an important sensor of oxidative stress, confers ferroptosis resistance through upregulation of genes involved in detoxification of excess iron and reactive oxygen species (ROS), revealing a mechanism of drug resistance in primary AML with unfavorable cytogenetics.

INSTRUMENT(S): Illumina NovaSeq 6000

ORGANISM(S): Homo sapiens

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PROVIDER: E-MTAB-9803 | biostudies-arrayexpress |

SECONDARY ACCESSION(S): ERP125424

REPOSITORIES: biostudies-arrayexpress

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