A recent study showed that targeting mitochondrial fusion was a new vulnerability of acute myeloid leukaemia (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-leukaemic activity, while having limited impact on normal hematopoietic cells. The findings of this study were recently published in Leukemia.
Acute myeloid leukaemia (AML) is a bone marrow-derived haematological cancer characterised by the expansion of immature myeloid cells. Interestingly, proteogenomic profiling on a large cohort of patients revealed a specific AML subtype characterised by high expression of mitochondrial proteins and lower remission/survival rates.1 Moreover, single-cell transcriptomics uncovered mitochondrial-driven adaptive resistance to chemotherapy, suggesting that targeting mitochondrial metabolism could improve therapeutic response in AML.2 Mitochondria are constantly reshaped to adapt to the bioenergetic requirements of the cell through fusion and fission involving the inner and outer mitochondrial membrane (IMM and OMM, respectively).3 These mitochondrial dynamics are tightly regulated by dynamin-related GTPase proteins, which include the mitofusin MFN2 and optic atrophy 1 (OPA1), involved in mitochondrial fusion tethering OMM (MFN2) and IMM (OPA1).
In the current study, MFN2 and OPA1 were depleted using doxycycline (Dox)-inducible shRNAs in two AML human cell lines (MOLM-14 and OCI-AML2).4 Depletion of the fusion effectors decreased mitochondrial size and significantly induced leukaemic cell death and inhibition of proliferation (p<0.001). Subsequently, MFN2 or OPA1 were depleted using mCherry-tagged constitutive shRNAs in leukaemic cells from patients with AML amplified in vivo using patient-derived xenograft (PDX) assays, or in normal human CD34+ hematopoietic progenitor cells. This resulted in a significant reduction of leukaemia colony formation (shMFN2, p<0.01)(shOPA1, p<0.05).
To complement these results, the researchers used the only currently available pharmacological inhibitor of mitochondrial fusion, the small compound OPA1 inhibitor MYLS22, which significantly reduced mitochondrial length (p<0.01) and decreased the viability of MOLM-14 cells by 40% . Finally, the researchers observed that seven days of in vivo treatment with MYLS22 significantly reduced tumour burden in leukaemia-bearing mice (p<0.01). Together, these results suggest that mitochondrial fusion is a new vulnerability in AML.