Project description:Mitochondrial metabolism recently emerged as a critical dependency in acute myeloid leukemia (AML). The shape of mitochondria is tightly regulated by dynamin GTPase proteins, which drive opposing fusion and fission forces to consistently adapt bioenergetics to the cellular context. Here, we showed that targeting mitochondrial structure through the inhibition of mitochondrial fusion was a new vulnerability of AML cells, when assayed in patient-derived xenograft (PDX) models. Genetic depletion of mitofusin 2 (MFN2) or optic atrophy 1 (OPA1) or pharmacological inhibition of OPA1 (MYLS22) blocked mitochondrial fusion and had significant anti-leukemic activity, while having limited impact on normal hematopoietic cells ex vivo and in vivo. Mechanistically, inhibition of mitochondrial fusion disrupted mitochondrial respiration and reactive oxygen species production, leading to cell cycle arrest at the G0/G1 transition. These results nominate the inhibition of mitochondrial fusion as a promising therapeutic approach for AML.
Project description:Mitochondrial metabolism recently emerged as a critical dependency in acute myeloid leukemia (AML). The shape of mitochondria is tightly regulated by dynamin GTPase proteins, which drive opposing fusion and fission forces to consistently adapt bioenergetics to the cellular context. Here, we showed that targeting mitochondrial structure through the inhibition of mitochondrial fusion was a new vulnerability of AML cells, when assayed in patient-derived xenograft (PDX) models. Genetic depletion of mitofusin 2 (MFN2) or optic atrophy 1 (OPA1) or pharmacological inhibition of OPA1 (MYLS22) blocked mitochondrial fusion and had significant anti-leukemic activity, while having limited impact on normal hematopoietic cells ex vivo and in vivo. Mechanistically, inhibition of mitochondrial fusion disrupted mitochondrial respiration and reactive oxygen species production, leading to cell cycle arrest at the G0/G1 transition. These results nominate the inhibition of mitochondrial fusion as a promising therapeutic approach for AML.
Project description:Mitochondrial metabolism recently emerged as a critical dependency in acute myeloid leukemia (AML). The shape of mitochondria is tightly regulated by dynamin GTPase proteins, which drive opposing fusion and fission forces to consistently adapt bioenergetics to the cellular context. Here, we showed that targeting mitochondrial structure through the inhibition of mitochondrial fusion was a new vulnerability of AML cells, when assayed in patient-derived xenograft (PDX) models. Genetic depletion of mitofusin 2 (MFN2) or optic atrophy 1 (OPA1) or pharmacological inhibition of OPA1 (MYLS22) blocked mitochondrial fusion and had significant anti-leukemic activity, while having limited impact on normal hematopoietic cells ex vivo and in vivo. Mechanistically, inhibition of mitochondrial fusion disrupted mitochondrial respiration and reactive oxygen species production, leading to cell cycle arrest at the G0/G1 transition. These results nominate the inhibition of mitochondrial fusion as a promising therapeutic approach for AML.
Project description:In acute myeloid leukemias (AML), chemotherapy is frequently followed by disease relapse, yet the mechanism by which AML reemerges is not fully understood. We hypothesized that chemotherapy induces senescence-like dormancy that facilitates survival to genotoxic exposure, allowing AML cells to endure treatment in a transiently dormant state while retaining potential for leukemic repopulation. Here, we show that primary AML cells exhibit hallmark senescence features following treatment with cytarabine (AraC), including growth arrest, increased cellular granularity, senescence-associated-β-galactosidase (SA-β-gal) activity, and senescence-associated transcriptomic alterations. Induction of AraC-induced premature senescence was regulated by the ATR kinase activity and mediated stress-survival. High-throughput single cell RNA (scRNA)-seq analysis of primary AML cells ex vivo and in vivo following chemotherapy suggest active transcriptional programming towards senescent-like dormancy instead of enrichment for leukemia stem cells (LSCs). scRNA-seq of sorted AraC-induced premature senescent AML cells demonstrated a heterogenous population including a fraction of cells with simultaneous expression of dormancy- and senescence-associated gene signatures. Xenotransplantation of AraC-induced premature senescent AML cells into mice demonstrated that senescent-like AML cells maintain leukemia-repopulating potential. Altogether, we propose a mechanism of AML relapse whereby AML cells tolerate chemotherapy via acquisition of a transient senescent-like state.