A novel small molecule that kills a subset of MLL-rearranged leukemia cells by inducing mitochondrial dysfunction PMID: 30670779

ADC Targets in Oncology

2026-04-10

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

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. [email protected].

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.