The creatine kinase pathway is a metabolic vulnerability in EVI1-positive acute myeloid leukemia

Nina Fenouille; Christopher F. Bassil; Issam Ben-Sahra; Lina Benajiba; Gabriela Alexe; Azucena Ramos; Yana Pikman; Amy S. Conway; Michael R. Burgess; Qing Li; Frédéric Luciano; Patrick Auberger; Ilene Galinsky; Daniel J. Deangelo; Richard M. Stone; Yi Zhang; Archibald S. Perkins; Kevin Shannon; Michael T. Hemann; Alexandre Puissant; Kimberly Stegmaier

doi:10.1038/nm.4283

The creatine kinase pathway is a metabolic vulnerability in EVI1-positive acute myeloid leukemia

Nina Fenouille, Christopher F. Bassil, Issam Ben-Sahra, Lina Benajiba, Gabriela Alexe, Azucena Ramos, Yana Pikman, Amy S. Conway, Michael R. Burgess, Qing Li, Frédéric Luciano, Patrick Auberger, Ilene Galinsky, Daniel J. Deangelo, Richard M. Stone, Yi Zhang, Archibald S. Perkins, Kevin Shannon, Michael T. Hemann, Alexandre PuissantKimberly Stegmaier^*

^*Corresponding author for this work

Biochemistry and Molecular Genetics

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

66 Scopus citations

Abstract

Expression of the MECOM (also known as EVI1) proto-oncogene is deregulated by chromosomal translocations in some cases of acute myeloid leukemia (AML) and is associated with poor clinical outcome. Here, through transcriptomic and metabolomic profiling of hematopoietic cells, we reveal that EVI1 overexpression alters cellular metabolism. A screen using pooled short hairpin RNAs (shRNAs) identified the ATP-buffering, mitochondrial creatine kinase CKMT1 as necessary for survival of EVI1-expressing cells in subjects with EVI1-positive AML. EVI1 promotes CKMT1 expression by repressing the myeloid differentiation regulator RUNX1. Suppression of arginine-creatine metabolism by CKMT1-directed shRNAs or by the small molecule cyclocreatine selectively decreased the viability, promoted the cell cycle arrest and apoptosis of human EVI1-positive cell lines, and prolonged survival in both orthotopic xenograft models and mouse models of primary AML. CKMT1 inhibition altered mitochondrial respiration and ATP production, an effect that was abrogated by phosphocreatine-mediated reactivation of the arginine-creatine pathway. Targeting CKMT1 is thus a promising therapeutic strategy for this EVI1-driven AML subtype that is highly resistant to current treatment regimens.

Original language	English (US)
Pages (from-to)	301-313
Number of pages	13
Journal	Nature Medicine
Volume	23
Issue number	3
DOIs	https://doi.org/10.1038/nm.4283
State	Published - Mar 1 2017

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)

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Fenouille, N., Bassil, C. F., Ben-Sahra, I., Benajiba, L., Alexe, G., Ramos, A., Pikman, Y., Conway, A. S., Burgess, M. R., Li, Q., Luciano, F., Auberger, P., Galinsky, I., Deangelo, D. J., Stone, R. M., Zhang, Y., Perkins, A. S., Shannon, K., Hemann, M. T., ... Stegmaier, K. (2017). The creatine kinase pathway is a metabolic vulnerability in EVI1-positive acute myeloid leukemia. Nature Medicine, 23(3), 301-313. https://doi.org/10.1038/nm.4283

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title = "The creatine kinase pathway is a metabolic vulnerability in EVI1-positive acute myeloid leukemia",

abstract = "Expression of the MECOM (also known as EVI1) proto-oncogene is deregulated by chromosomal translocations in some cases of acute myeloid leukemia (AML) and is associated with poor clinical outcome. Here, through transcriptomic and metabolomic profiling of hematopoietic cells, we reveal that EVI1 overexpression alters cellular metabolism. A screen using pooled short hairpin RNAs (shRNAs) identified the ATP-buffering, mitochondrial creatine kinase CKMT1 as necessary for survival of EVI1-expressing cells in subjects with EVI1-positive AML. EVI1 promotes CKMT1 expression by repressing the myeloid differentiation regulator RUNX1. Suppression of arginine-creatine metabolism by CKMT1-directed shRNAs or by the small molecule cyclocreatine selectively decreased the viability, promoted the cell cycle arrest and apoptosis of human EVI1-positive cell lines, and prolonged survival in both orthotopic xenograft models and mouse models of primary AML. CKMT1 inhibition altered mitochondrial respiration and ATP production, an effect that was abrogated by phosphocreatine-mediated reactivation of the arginine-creatine pathway. Targeting CKMT1 is thus a promising therapeutic strategy for this EVI1-driven AML subtype that is highly resistant to current treatment regimens.",

author = "Nina Fenouille and Bassil, {Christopher F.} and Issam Ben-Sahra and Lina Benajiba and Gabriela Alexe and Azucena Ramos and Yana Pikman and Conway, {Amy S.} and Burgess, {Michael R.} and Qing Li and Fr{\'e}d{\'e}ric Luciano and Patrick Auberger and Ilene Galinsky and Deangelo, {Daniel J.} and Stone, {Richard M.} and Yi Zhang and Perkins, {Archibald S.} and Kevin Shannon and Hemann, {Michael T.} and Alexandre Puissant and Kimberly Stegmaier",

note = "Publisher Copyright: {\textcopyright} 2017 Nature America, Inc., part of Springer Nature.",

year = "2017",

month = mar,

day = "1",

doi = "10.1038/nm.4283",

language = "English (US)",

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Fenouille, N, Bassil, CF, Ben-Sahra, I, Benajiba, L, Alexe, G, Ramos, A, Pikman, Y, Conway, AS, Burgess, MR, Li, Q, Luciano, F, Auberger, P, Galinsky, I, Deangelo, DJ, Stone, RM, Zhang, Y, Perkins, AS, Shannon, K, Hemann, MT, Puissant, A & Stegmaier, K 2017, 'The creatine kinase pathway is a metabolic vulnerability in EVI1-positive acute myeloid leukemia', Nature Medicine, vol. 23, no. 3, pp. 301-313. https://doi.org/10.1038/nm.4283

TY - JOUR

T1 - The creatine kinase pathway is a metabolic vulnerability in EVI1-positive acute myeloid leukemia

AU - Fenouille, Nina

AU - Bassil, Christopher F.

AU - Ben-Sahra, Issam

AU - Benajiba, Lina

AU - Alexe, Gabriela

AU - Ramos, Azucena

AU - Pikman, Yana

AU - Conway, Amy S.

AU - Burgess, Michael R.

AU - Li, Qing

AU - Luciano, Frédéric

AU - Auberger, Patrick

AU - Galinsky, Ilene

AU - Deangelo, Daniel J.

AU - Stone, Richard M.

AU - Zhang, Yi

AU - Perkins, Archibald S.

AU - Shannon, Kevin

AU - Hemann, Michael T.

AU - Puissant, Alexandre

AU - Stegmaier, Kimberly

PY - 2017/3/1

Y1 - 2017/3/1

N2 - Expression of the MECOM (also known as EVI1) proto-oncogene is deregulated by chromosomal translocations in some cases of acute myeloid leukemia (AML) and is associated with poor clinical outcome. Here, through transcriptomic and metabolomic profiling of hematopoietic cells, we reveal that EVI1 overexpression alters cellular metabolism. A screen using pooled short hairpin RNAs (shRNAs) identified the ATP-buffering, mitochondrial creatine kinase CKMT1 as necessary for survival of EVI1-expressing cells in subjects with EVI1-positive AML. EVI1 promotes CKMT1 expression by repressing the myeloid differentiation regulator RUNX1. Suppression of arginine-creatine metabolism by CKMT1-directed shRNAs or by the small molecule cyclocreatine selectively decreased the viability, promoted the cell cycle arrest and apoptosis of human EVI1-positive cell lines, and prolonged survival in both orthotopic xenograft models and mouse models of primary AML. CKMT1 inhibition altered mitochondrial respiration and ATP production, an effect that was abrogated by phosphocreatine-mediated reactivation of the arginine-creatine pathway. Targeting CKMT1 is thus a promising therapeutic strategy for this EVI1-driven AML subtype that is highly resistant to current treatment regimens.

AB - Expression of the MECOM (also known as EVI1) proto-oncogene is deregulated by chromosomal translocations in some cases of acute myeloid leukemia (AML) and is associated with poor clinical outcome. Here, through transcriptomic and metabolomic profiling of hematopoietic cells, we reveal that EVI1 overexpression alters cellular metabolism. A screen using pooled short hairpin RNAs (shRNAs) identified the ATP-buffering, mitochondrial creatine kinase CKMT1 as necessary for survival of EVI1-expressing cells in subjects with EVI1-positive AML. EVI1 promotes CKMT1 expression by repressing the myeloid differentiation regulator RUNX1. Suppression of arginine-creatine metabolism by CKMT1-directed shRNAs or by the small molecule cyclocreatine selectively decreased the viability, promoted the cell cycle arrest and apoptosis of human EVI1-positive cell lines, and prolonged survival in both orthotopic xenograft models and mouse models of primary AML. CKMT1 inhibition altered mitochondrial respiration and ATP production, an effect that was abrogated by phosphocreatine-mediated reactivation of the arginine-creatine pathway. Targeting CKMT1 is thus a promising therapeutic strategy for this EVI1-driven AML subtype that is highly resistant to current treatment regimens.

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DO - 10.1038/nm.4283

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VL - 23

SP - 301

EP - 313

JO - Nature Medicine

JF - Nature Medicine

IS - 3

ER -

The creatine kinase pathway is a metabolic vulnerability in EVI1-positive acute myeloid leukemia

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