2. Academic Validation
  3. A novel small molecule that kills a subset of MLL-rearranged leukemia cells by inducing mitochondrial dysfunction

A novel small molecule that kills a subset of MLL-rearranged leukemia cells by inducing mitochondrial dysfunction

  • Oncogene. 2019 May;38(20):3824-3842. doi: 10.1038/s41388-018-0666-5.
Klaartje Somers 1,  Victoria W Wen 1,  Shiloh M C Middlemiss 1,  Brenna Osborne 2,  Helen Forgham 1 3,  MoonSun Jung 1,  Mawar Karsa 1,  Molly Clifton 1,  Angelika Bongers 1,  Jixuan Gao 1,  Chelsea Mayoh 1,  Newsha Raoufi-Rad 1,  Eric P Kusnadi 4,  Kate M Hannan 5,  David A Scott 6,  Alan Kwek 1,  Bing Liu 1,  Claudia Flemming 1,  Daria A Chudakova 1,  Ruby Pandher 1,  Tim W Failes 1 7,  James Lim 1,  Andrea Angeli 8,  Andrei L Osterman 6,  Toshihiko Imamura 9,  Ursula R Kees 10,  Claudiu T Supuran 8,  Richard B Pearson 4,  Ross D Hannan 5,  Thomas P Davis 11 12,  Joshua McCarroll 1 3,  Maria Kavallaris 1 3,  Nigel Turner 2,  Andrei V Gudkov 13 14,  Michelle Haber 1,  Murray D Norris 1 15,  Michelle J Henderson 16
Affiliations

Affiliations

  • 1 Children's Cancer Institute, Lowy Cancer Research Centre, UNSW, Randwick, NSW, Australia.
  • 2 Mitochondrial Bioenergetics Laboratory, School of Medical Sciences, UNSW, Randwick, NSW, Australia.
  • 3 ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Australian Centre for NanoMedicine, UNSW Australia, Sydney, NSW, Australia.
  • 4 Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
  • 5 The John Curtin School of Medical Research, The Australian National University, Canberra City, ACT, Australia.
  • 6 Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, 92037, USA.
  • 7 ACRF Drug Discovery Centre, Children's Cancer Institute, Lowy Cancer Research Centre, UNSW, Sydney, New South Wales, Australia.
  • 8 Neurofarba Department, University of Florence, Florence, Italy.
  • 9 Department of Pediatrics, Kyoto Prefectural University of Medicine, Kyoto, Japan.
  • 10 Telethon Kids Institute, University of Western Australia, Perth, WA, Australia.
  • 11 ARC Centre of Excellence in Convergent Bio-Nano Science and Technology Monash Institute of Pharmaceutical Sciences, Monash University, Clayton, VIC, Australia.
  • 12 Department of Chemistry, University of Warrick, Coventry, UK.
  • 13 Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY, USA.
  • 14 Oncotartis, Inc., Buffalo, NY, USA.
  • 15 UNSW Centre for Childhood Cancer Research, Sydney, NSW, Australia.
  • 16 Children's Cancer Institute, Lowy Cancer Research Centre, UNSW, Randwick, NSW, Australia. mhenderson@ccia.unsw.edu.au.
PMID: 30670779 DOI: 10.1038/s41388-018-0666-5
Abstract

Survival rates for pediatric patients suffering from mixed lineage leukemia (MLL)-rearranged leukemia remain below 50% and more targeted, less toxic therapies are urgently needed. A screening method optimized to discover cytotoxic compounds selective for MLL-rearranged leukemia identified CCI-006 as a novel inhibitor of MLL-rearranged and CALM-AF10 translocated leukemias that share common leukemogenic pathways. CCI-006 inhibited mitochondrial respiration and induced mitochondrial membrane depolarization and Apoptosis in a subset (7/11, 64%) of MLL-rearranged leukemia cell lines within a few hours of treatment. The unresponsive MLL-rearranged leukemia cells did not undergo mitochondrial membrane depolarization or Apoptosis despite a similar attenuation of mitochondrial respiration by the compound. In comparison to the sensitive cells, the unresponsive MLL-rearranged leukemia cells were characterized by a more glycolytic metabolic phenotype, exemplified by a more pronounced sensitivity to glycolysis inhibitors and elevated HIF1α expression. Silencing of HIF1α expression sensitized an intrinsically unresponsive MLL-rearranged leukemia cell to CCI-006, indicating that this pathway plays a role in determining sensitivity to the compound. In addition, unresponsive MLL-rearranged leukemia cells expressed increased levels of MEIS1, an important leukemogenic MLL target gene that plays a role in regulating metabolic phenotype through HIF1α. MEIS1 expression was also variable in a pediatric MLL-rearranged ALL patient dataset, highlighting the existence of a previously undescribed metabolic variability in MLL-rearranged leukemia that may contribute to the heterogeneity of the disease. This study thus identified a novel small molecule that rapidly kills MLL-rearranged leukemia cells by targeting a metabolic vulnerability in a subset of low HIF1α/low MEIS1-expressing MLL-rearranged leukemia cells.

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