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 HIF1 alpha expression. Silencing of HIF1 alpha 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 HIF1 alpha. 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 HIF1 alpha/low MEIS1-expressing MLL-rearranged leukemia cells.
| Original language | English |
|---|---|
| Pages (from-to) | 3824-3842 |
| Number of pages | 19 |
| Journal | Oncogene |
| Volume | 38 |
| Issue number | 20 |
| DOIs | |
| Publication status | Published - 16 May 2019 |
Cite this
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A novel small molecule that kills a subset of MLL-rearranged leukemia cells by inducing mitochondrial dysfunction. / Somers, Klaartje; Wen, Victoria W.; Middlemiss, Shiloh M. C.; Osborne, Brenna; Forgham, Helen; Jung, MoonSun; Karsa, Mawar; Clifton, Molly; Bongers, Angelika; Gao, Jixuan; Mayoh, Chelsea; Raoufi-Rad, Newsha; Kusnadi, Eric P.; Hannan, Kate M.; Scott, David A.; Kwek, Alan; Liu, Bing; Flemming, Claudia; Chudakova, Daria A.; Pandher, Ruby; Failes, Tim W.; Lim, James; Angeli, Andrea; Osterman, Andrei L.; Imamura, Toshihiko; Kees, Ursula R.; Supuran, Claudiu T.; Pearson, Richard B.; Hannan, Ross D.; Davis, Thomas P.; McCarroll, Joshua; Kavallaris, Maria; Turner, Nigel; Gudkov, Andrei V.; Haber, Michelle; Norris, Murray D.; Henderson, Michelle J.
In: Oncogene, Vol. 38, No. 20, 16.05.2019, p. 3824-3842.Research output: Contribution to journal › Article
TY - JOUR
T1 - A novel small molecule that kills a subset of MLL-rearranged leukemia cells by inducing mitochondrial dysfunction
AU - Somers, Klaartje
AU - Wen, Victoria W.
AU - Middlemiss, Shiloh M. C.
AU - Osborne, Brenna
AU - Forgham, Helen
AU - Jung, MoonSun
AU - Karsa, Mawar
AU - Clifton, Molly
AU - Bongers, Angelika
AU - Gao, Jixuan
AU - Mayoh, Chelsea
AU - Raoufi-Rad, Newsha
AU - Kusnadi, Eric P.
AU - Hannan, Kate M.
AU - Scott, David A.
AU - Kwek, Alan
AU - Liu, Bing
AU - Flemming, Claudia
AU - Chudakova, Daria A.
AU - Pandher, Ruby
AU - Failes, Tim W.
AU - Lim, James
AU - Angeli, Andrea
AU - Osterman, Andrei L.
AU - Imamura, Toshihiko
AU - Kees, Ursula R.
AU - Supuran, Claudiu T.
AU - Pearson, Richard B.
AU - Hannan, Ross D.
AU - Davis, Thomas P.
AU - McCarroll, Joshua
AU - Kavallaris, Maria
AU - Turner, Nigel
AU - Gudkov, Andrei V.
AU - Haber, Michelle
AU - Norris, Murray D.
AU - Henderson, Michelle J.
PY - 2019/5/16
Y1 - 2019/5/16
N2 - 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 HIF1 alpha expression. Silencing of HIF1 alpha 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 HIF1 alpha. 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 HIF1 alpha/low MEIS1-expressing MLL-rearranged leukemia cells.
AB - 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 HIF1 alpha expression. Silencing of HIF1 alpha 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 HIF1 alpha. 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 HIF1 alpha/low MEIS1-expressing MLL-rearranged leukemia cells.
KW - TARGETING MITOCHONDRIA
KW - THERAPEUTIC STRATEGY
KW - CARBONIC-ANHYDRASES
KW - OXIDATIVE STRESS
KW - MEIS1
KW - CANCER
KW - INHIBITION
KW - EXPRESSION
KW - METABOLISM
KW - TRANSLOCATIONS
U2 - 10.1038/s41388-018-0666-5
DO - 10.1038/s41388-018-0666-5
M3 - Article
VL - 38
SP - 3824
EP - 3842
JO - Oncogene
JF - Oncogene
SN - 0950-9232
IS - 20
ER -