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

Klaartje Somers; Victoria W. Wen; Shiloh M. C. Middlemiss; Brenna Osborne; Helen Forgham; MoonSun Jung; Mawar Karsa; Molly Clifton; Angelika Bongers; Jixuan Gao; Chelsea Mayoh; Newsha Raoufi-Rad; Eric P. Kusnadi; Kate M. Hannan; David A. Scott; Alan Kwek; Bing Liu; Claudia Flemming; Daria A. Chudakova; Ruby Pandher; Tim W. Failes; James Lim; Andrea Angeli; Andrei L. Osterman; Toshihiko Imamura; Ursula R. Kees; Claudiu T. Supuran; Richard B. Pearson; Ross D. Hannan; Thomas P. Davis; Joshua McCarroll; Maria Kavallaris; Nigel Turner; Andrei V. Gudkov; Michelle Haber; Murray D. Norris; Michelle J. Henderson

doi:10.1038/s41388-018-0666-5

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

Klaartje Somers, Victoria W. Wen, Shiloh M. C. Middlemiss, Brenna Osborne, Helen Forgham, MoonSun Jung, Mawar Karsa, Molly Clifton, Angelika Bongers, Jixuan Gao, Chelsea Mayoh, Newsha Raoufi-Rad, Eric P. Kusnadi, Kate M. Hannan, David A. Scott, Alan Kwek, Bing Liu, Claudia Flemming, Daria A. Chudakova, Ruby PandherTim W. Failes, James Lim, Andrea Angeli, Andrei L. Osterman, Toshihiko Imamura, Ursula R. Kees, Claudiu T. Supuran, Richard B. Pearson, Ross D. Hannan, Thomas P. Davis, Joshua McCarroll, Maria Kavallaris, Nigel Turner, Andrei V. Gudkov, Michelle Haber, Murray D. Norris, Michelle J. Henderson

Paediatrics

Research output: Contribution to journal › Article › peer-review

14 Citations (Scopus)

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	https://doi.org/10.1038/s41388-018-0666-5
Publication status	Published - 16 May 2019

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10.1038/s41388-018-0666-5

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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(20), 3824-3842. https://doi.org/10.1038/s41388-018-0666-5

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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 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.",

keywords = "TARGETING MITOCHONDRIA, THERAPEUTIC STRATEGY, CARBONIC-ANHYDRASES, OXIDATIVE STRESS, MEIS1, CANCER, INHIBITION, EXPRESSION, METABOLISM, TRANSLOCATIONS",

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 = "16",

doi = "10.1038/s41388-018-0666-5",

language = "English",

volume = "38",

pages = "3824--3842",

journal = "Oncogene",

issn = "0950-9232",

publisher = "Nature Publishing Group",

number = "20",

}

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, vol. 38, no. 20, pp. 3824-3842. https://doi.org/10.1038/s41388-018-0666-5

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

C2 - 30670779

SN - 0950-9232

VL - 38

SP - 3824

EP - 3842

JO - Oncogene

JF - Oncogene

IS - 20

ER -

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

Abstract

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