Oncotarget

Research Papers:

CCI-007, a novel small molecule with cytotoxic activity against infant leukemia with MLL rearrangements

Klaartje Somers, Daria A. Chudakova, Shiloh M.C. Middlemiss, Victoria W. Wen, Molly Clifton, Alan Kwek, Bing Liu, Chelsea Mayoh, Angelika Bongers, Mawar Karsa, Sukey Pan, Sarah Cruikshank, Marissa Scandlyn, Wendi Hoang, Toshihiko Imamura, Ursula R. Kees, Andrei V. Gudkov, Olga B. Chernova, Michelle Haber, Murray D. Norris and Michelle J. Henderson _

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Oncotarget. 2016; 7:46067-46087. https://doi.org/10.18632/oncotarget.10022

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Abstract

Klaartje Somers1,*, Daria A. Chudakova1,*, Shiloh M.C. Middlemiss1, Victoria W. Wen1, Molly Clifton1, Alan Kwek1, Bing Liu1, Chelsea Mayoh1, Angelika Bongers1, Mawar Karsa1, Sukey Pan1, Sarah Cruikshank1, Marissa Scandlyn1, Wendi Hoang1, Toshihiko Imamura2, Ursula R. Kees3, Andrei V. Gudkov4,5, Olga B. Chernova5, Michelle Haber1,, Murray D. Norris1,, Michelle J. Henderson1,

1Children’s Cancer Institute, University of New South Wales, Sydney, New South Wales, Australia

2Department of Pediatrics, Kyoto Prefectural University of Medicine, Kyoto, Japan

3Telethon Kids Institute, University of Western Australia, Perth, Western Australia, Australia

4Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY, USA

5Oncotartis, Inc., Buffalo, NY, USA

*These authors have contributed equally to this work

These authors have contributed equally to this work

Correspondence to:

Michelle J. Henderson, email: Mhenderson@ccia.unsw.edu.au

Keywords: MLL-rearranged leukemia, CALM-AF10 leukemia, HOXA9/MEIS pathway, small molecule, apoptosis

Received: December 15, 2015     Accepted: May 28, 2016     Published: June 14, 2016

ABSTRACT

There is an urgent need for the development of less toxic, more selective and targeted therapies for infants with leukemia characterized by translocation of the mixed lineage leukemia (MLL) gene. In this study, we performed a cell-based small molecule library screen on an infant MLL-rearranged (MLL-r) cell line, PER-485, in order to identify selective inhibitors for MLL-r leukemia. After screening initial hits for a cytotoxic effect against a panel of 30 cell lines including MLL-r and MLL wild-type (MLL-wt) leukemia, solid tumours and control cells, small molecule CCI-007 was identified as a compound that selectively and significantly decreased the viability of a subset of MLL-r and related leukemia cell lines with CALM-AF10 and SET-NUP214 translocation. CCI-007 induced a rapid caspase-dependent apoptosis with mitochondrial depolarization within twenty-four hours of treatment. CCI-007 altered the characteristic MLL-r gene expression signature in sensitive cells with downregulation of the expression of HOXA9, MEIS1, CMYC and BCL2, important drivers in MLL-r leukemia, within a few hours of treatment. MLL-r leukemia cells that were resistant to the compound were characterised by significantly higher baseline gene expression levels of MEIS1 and BCL2 in comparison to CCI-007 sensitive MLL-r leukemia cells.

In conclusion, we have identified CCI-007 as a novel small molecule that displays rapid toxicity towards a subset of MLL-r, CALM-AF10 and SET-NUP214 leukemia cell lines. Our findings suggest an important new avenue in the development of targeted therapies for these deadly diseases and indicate that different therapeutic strategies might be needed for different subtypes of MLL-r leukemia.


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