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

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt

Standard

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.

I: Oncogene, Bind 38, 22.05.2019, s. 3824–3842.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt

Harvard

Somers, K, Wen, VW, Middlemiss, SMC, Osborne, B, Forgham, H, Jung, M, Karsa, M, Clifton, M, Bongers, A, Gao, J, Mayoh, C, Raoufi-Rad, N, Kusnadi, EP, Hannan, KM, Scott, DA, Kwek, A, Liu, B, Flemming, C, Chudakova, DA, Pandher, R, Failes, TW, Lim, J, Angeli, A, Osterman, AL, Imamura, T, Kees, UR, Supuran, CT, Pearson, RB, Hannan, RD, Davis, TP, McCarroll, J, Kavallaris, M, Turner, N, Gudkov, AV, Haber, M, Norris, MD & Henderson, MJ 2019, 'A novel small molecule that kills a subset of MLL-rearranged leukemia cells by inducing mitochondrial dysfunction', Oncogene, bind 38, s. 3824–3842. https://doi.org/10.1038/s41388-018-0666-5

APA

Somers, K., Wen, V. W., Middlemiss, S. M. C., Osborne, B., Forgham, H., Jung, M., Karsa, M., Clifton, M., Bongers, A., Gao, J., Mayoh, C., Raoufi-Rad, N., Kusnadi, E. P., Hannan, K. M., Scott, D. A., Kwek, A., Liu, B., Flemming, C., Chudakova, D. A., ... Henderson, M. J. (2019). A novel small molecule that kills a subset of MLL-rearranged leukemia cells by inducing mitochondrial dysfunction. Oncogene, 38, 3824–3842. https://doi.org/10.1038/s41388-018-0666-5

Vancouver

Somers K, Wen VW, Middlemiss SMC, Osborne B, Forgham H, Jung M o.a. A novel small molecule that kills a subset of MLL-rearranged leukemia cells by inducing mitochondrial dysfunction. Oncogene. 2019 maj 22;38:3824–3842. https://doi.org/10.1038/s41388-018-0666-5

Author

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. / A novel small molecule that kills a subset of MLL-rearranged leukemia cells by inducing mitochondrial dysfunction. I: Oncogene. 2019 ; Bind 38. s. 3824–3842.

Bibtex

@article{3e88b05f5eee4cb09993d25919f910ea,
title = "A novel small molecule that kills a subset of MLL-rearranged leukemia cells by inducing mitochondrial dysfunction",
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.",
author = "Klaartje Somers and Wen, {Victoria W.} and Middlemiss, {Shiloh M. C.} and Brenna Osborne and Helen Forgham and MoonSun Jung and Mawar Karsa and Molly Clifton and Angelika Bongers and Jixuan Gao and Chelsea Mayoh and Newsha Raoufi-Rad and Kusnadi, {Eric P.} and Hannan, {Kate M.} and Scott, {David A.} and Alan Kwek and Bing Liu and Claudia Flemming and Chudakova, {Daria A.} and Ruby Pandher and Failes, {Tim W.} and James Lim and Andrea Angeli and Osterman, {Andrei L.} and Toshihiko Imamura and Kees, {Ursula R.} and Supuran, {Claudiu T.} and Pearson, {Richard B.} and Hannan, {Ross D.} and Davis, {Thomas P.} and Joshua McCarroll and Maria Kavallaris and Nigel Turner and Gudkov, {Andrei V.} and Michelle Haber and Norris, {Murray D.} and Henderson, {Michelle J.}",
year = "2019",
month = may,
day = "22",
doi = "10.1038/s41388-018-0666-5",
language = "English",
volume = "38",
pages = "3824–3842",
journal = "Oncogene",
issn = "0950-9232",
publisher = "nature publishing group",

}

RIS

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 - 2019/5/22

Y1 - 2019/5/22

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 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.

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 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.

U2 - 10.1038/s41388-018-0666-5

DO - 10.1038/s41388-018-0666-5

M3 - Journal article

VL - 38

SP - 3824

EP - 3842

JO - Oncogene

JF - Oncogene

SN - 0950-9232

ER -

ID: 291673038