CCI-007, a novel small molecule with cytotoxic activity against infant leukemia with MLL rearrangements.
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.
Children's Cancer Institute, University of New South Wales, Sydney, New South Wales, Australia.
Klaartje
K
Somers
Children's Cancer Institute, University of New South Wales, Sydney, New South Wales, Australia.
Daria A
DA
Chudakova
Children's Cancer Institute, University of New South Wales, Sydney, New South Wales, Australia.
Shiloh M C
SM
Middlemiss
Children's Cancer Institute, University of New South Wales, Sydney, New South Wales, Australia.
Victoria W
VW
Wen
Children's Cancer Institute, University of New South Wales, Sydney, New South Wales, Australia.
Molly
M
Clifton
Children's Cancer Institute, University of New South Wales, Sydney, New South Wales, Australia.
Alan
A
Kwek
Children's Cancer Institute, University of New South Wales, Sydney, New South Wales, Australia.
Bing
B
Liu
Children's Cancer Institute, University of New South Wales, Sydney, New South Wales, Australia.
Chelsea
C
Mayoh
Children's Cancer Institute, University of New South Wales, Sydney, New South Wales, Australia.
Angelika
A
Bongers
Children's Cancer Institute, University of New South Wales, Sydney, New South Wales, Australia.
Mawar
M
Karsa
Children's Cancer Institute, University of New South Wales, Sydney, New South Wales, Australia.
Sukey
S
Pan
Children's Cancer Institute, University of New South Wales, Sydney, New South Wales, Australia.
Sarah
S
Cruikshank
Children's Cancer Institute, University of New South Wales, Sydney, New South Wales, Australia.
Marissa
M
Scandlyn
Children's Cancer Institute, University of New South Wales, Sydney, New South Wales, Australia.
Wendi
W
Hoang
Department of Pediatrics, Kyoto Prefectural University of Medicine, Kyoto, Japan.
Toshihiko
T
Imamura
Telethon Kids Institute, University of Western Australia, Perth, Western Australia, Australia.
Ursula R
UR
Kees
Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY, USA.|Oncotartis, Inc., Buffalo, NY, USA.
Andrei V
AV
Gudkov
Oncotartis, Inc., Buffalo, NY, USA.
Olga B
OB
Chernova
Children's Cancer Institute, University of New South Wales, Sydney, New South Wales, Australia.
Michelle
M
Haber
Children's Cancer Institute, University of New South Wales, Sydney, New South Wales, Australia.
Murray D
MD
Norris
Children's Cancer Institute, University of New South Wales, Sydney, New South Wales, Australia.
Michelle J
MJ
Henderson
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins; D004354:Drug Screening Assays, Antitumor; D015870:Gene Expression / Q000187:drug effects; D056488:Histone Chaperones / Q000235:genetics; D006801:Humans; D007223:Infant; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics; D028861:Nuclear Pore Complex Proteins / Q000235:genetics; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics
C114359:AF10-CALM fusion protein, human; D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D056488:Histone Chaperones; C085914:NUP214 protein, human; D028861:Nuclear Pore Complex Proteins; D015514:Oncogene Proteins, Fusion; C513473:SET protein, human; D014157:Transcription Factors; D051788:Myeloid-Lymphoid Leukemia Protein
CALM-AF10 leukemia; HOXA9/MEIS pathway; MLL-rearranged leukemia; apoptosis; small molecule