IRON-SULFUR CLUSTER BIOGENESIS AND HEME METABOLISM ARE ESSENTIAL FOR RESIDUAL DISEASE IN AML

Mitochondrial activities, bioenergetics, dynamics and structure are crucial regulators of response and resistance to therapies in cancer including acute myeloid leukemia (AML). However, while cellular and systemic iron might contribute to mitochondrial functions and inflammation. the role of iron metabolism remains still largely unknown in the context of AML and/or drug resistance. Here, we first observed an increase in mitochondrial iron content in residual disease (RD) post-chemotherapy cytarabine in vitro and in vivo. Since mitochondrial iron takes a part for heme and iron-sulfur cluster (ISC) biogenesis, we noted that porphyrin biosynthesis and ISC machinery was stimulated in RD. Furthermore, activities of aconitase and ETCII, two mitochondrial ISC enzymes, were enhanced. Multi-omics analysis showed that Eltrombopag (ELT) was a potent modifying agent of mitochondrial iron balance, altering heme and ISC biosynthesis that led in turn to changes in energetic balance (OxPHOS, TCA cycle and carbon metabolism) and overcome AraC resistance in AML in vitro and in vivo. Importantly, we analyzed ex vivo response to doublet therapy AraC/ELT using primary AML samples and we observed that AML cells harboring TP53 mutations exhibited a good response to this doublet therapy. Accordingly, TP53-mutated AML models were more sensitive to AraC/ELT compared to TP53-wt AML models. Finally, bone marrow-associated macrophages were specifically modified and educated by TP53-driven tumors. Together, our results uncover heme/porphyrin and ISC biosynthetic pathways as targetable and critical pathways for maintaining an elevated OxPHOS in RD in an inflammatory macrophage-dependent manner.