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Ferritinophagy is a Druggable Vulnerability of Quiescent Leukemic Stem Cells in Acute Myeloid Leukemia

ABSTRACT: Acute myeloid leukemia (AML) remains a challenging hematological malignancy with poor prognosis and limited treatment options. Post-therapy relapse, particularly driven by leukemic stem cells (LSCs), contributes to therapeutic failure and adverse outcome. Here, we investigated the role of quiescence and its associated molecular mechanisms in AML pathogenesis and identified potential vulnerabilities for therapeutic intervention. We found that quiescent AML cells, enriched for LSC functions, exhibited a distinct gene set that served as a significant prognostic factor for poor outcomes in AML patients. Furthermore, quiescent cells displayed heightened autophagic activity, with a reliance on ferritinophagy, a selective form of autophagy mediated by Nuclear Receptor Coactivator 4 (NCOA4), for iron bioavailability. Inhibition of NCOA4 genetically or chemically showed potent anti-leukemic effects, particularly targeting the LSC compartment. These findings uncover that ferritinophagy inhibition may represent a promising therapeutic strategy for patients with AML.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Leukocyte, Bone Marrow

DISEASE(S): Acute Leukemia

SUBMITTER: jerome Tamburini

LAB HEAD: Jerome Tamburini

PROVIDER: PXD042796 | Pride | 2024-06-13

REPOSITORIES: Pride

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	20220221_LU50HMC83_pl22011_CL_01.raw	Raw
	20220221_LU50HMC84_pl22011_CL_04.raw	Raw
	20220221_LU50HMC86_pl22011_CL_05.raw	Raw
	20220221_LU50HMC87_pl22011_CL_02.raw	Raw
	20220221_LU50HMC89_pl22011_CL_03.raw	Raw

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Ferritinophagy is a Druggable Vulnerability of Quiescent Leukemic Stem Cells [9a]

Project description:Acute myeloid leukemia (AML) remains a challenging hematological malignancy with poor prognosis and limited treatment options. Post-therapy relapse, particularly driven by leukemic stem cells (LSCs), contributes to therapeutic failure and adverse outcome. Here, we investigated the role of quiescence and its associated molecular mechanisms in AML pathogenesis and identified potential vulnerabilities for therapeutic intervention. We found that quiescent AML cells, enriched for LSC functions, exhibited a distinct gene set that served as a significant prognostic factor for poor outcomes in AML patients. Furthermore, quiescent cells displayed heightened autophagic activity, with a reliance on ferritinophagy, a selective form of autophagy mediated by Nuclear Receptor Coactivator 4 (NCOA4), for iron bioavailability. Inhibition of NCOA4 genetically or chemically showed potent anti-leukemic effects, particularly targeting the LSC compartment. These findings uncover that ferritinophagy inhibition may represent a promising therapeutic strategy for patients with AML.

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