Inhibitory effects of SEL201 in acute myeloid leukemia

Ewa M. Kosciuczuk; Aroop K. Kar; Gavin T. Blyth; Mariafausta Fischietti; Sameem Abedin; Alain A. Mina; Rebekah Siliezar; Tomasz Rzymski; Krzysztof Brzozka; Elizabeth A. Eklund; Elspeth M. Beauchamp; Frank Eckerdt; Diana Saleiro; Leonidas C. Platanias

doi:10.18632/oncotarget.27388

Inhibitory effects of SEL201 in acute myeloid leukemia

Ewa M. Kosciuczuk, Aroop K. Kar, Gavin T. Blyth, Mariafausta Fischietti, Sameem Abedin, Alain A. Mina, Rebekah Siliezar, Tomasz Rzymski, Krzysztof Brzozka, Elizabeth A. Eklund, Elspeth M. Beauchamp, Frank Eckerdt, Diana Saleiro, Leonidas C. Platanias^*

^*Corresponding author for this work

Medicine, Hematology Oncology Division

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

9 Scopus citations

Abstract

MAPK interacting kinase (MNK), a downstream effector of mitogen-activated protein kinase (MAPK) pathways, activates eukaryotic translation initiation factor 4E (eIF4E) and plays a key role in the mRNA translation of mitogenic and antiapoptotic genes in acute myeloid leukemia (AML) cells. We examined the antileukemic properties of a novel MNK inhibitor, SEL201. Our studies provide evidence that SEL201 suppresses eIF4E phosphorylation on Ser209 in AML cell lines and in primary patient-derived AML cells. Such effects lead to growth inhibitory effects and leukemic cell apoptosis, as well as suppression of leukemic progenitor colony formation. Combination of SEL201 with 5'-azacytidine or rapamycin results in synergistic inhibition of AML cell growth. Collectively, these results suggest that SEL201 has significant antileukemic activity and further underscore the relevance of the MNK pathway in leukemogenesis.

Original language	English (US)
Pages (from-to)	7112-7121
Number of pages	10
Journal	Oncotarget
Volume	10
Issue number	67
DOIs	https://doi.org/10.18632/oncotarget.27388
State	Published - 2019

Keywords

Acute myeloid leukemia
EIF4E
Kinase inhibitor
MNK
SEL201

ASJC Scopus subject areas

Oncology

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10.18632/oncotarget.27388

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@article{314253ebf5824d13b007c7fb7a2daa82,

title = "Inhibitory effects of SEL201 in acute myeloid leukemia",

abstract = "MAPK interacting kinase (MNK), a downstream effector of mitogen-activated protein kinase (MAPK) pathways, activates eukaryotic translation initiation factor 4E (eIF4E) and plays a key role in the mRNA translation of mitogenic and antiapoptotic genes in acute myeloid leukemia (AML) cells. We examined the antileukemic properties of a novel MNK inhibitor, SEL201. Our studies provide evidence that SEL201 suppresses eIF4E phosphorylation on Ser209 in AML cell lines and in primary patient-derived AML cells. Such effects lead to growth inhibitory effects and leukemic cell apoptosis, as well as suppression of leukemic progenitor colony formation. Combination of SEL201 with 5'-azacytidine or rapamycin results in synergistic inhibition of AML cell growth. Collectively, these results suggest that SEL201 has significant antileukemic activity and further underscore the relevance of the MNK pathway in leukemogenesis.",

keywords = "Acute myeloid leukemia, EIF4E, Kinase inhibitor, MNK, SEL201",

author = "Kosciuczuk, {Ewa M.} and Kar, {Aroop K.} and Blyth, {Gavin T.} and Mariafausta Fischietti and Sameem Abedin and Mina, {Alain A.} and Rebekah Siliezar and Tomasz Rzymski and Krzysztof Brzozka and Eklund, {Elizabeth A.} and Beauchamp, {Elspeth M.} and Frank Eckerdt and Diana Saleiro and Platanias, {Leonidas C.}",

note = "Funding Information: This work was supported by the Northwestern University – Flow Cytometry Core Facility supported by Cancer Center Support Grant (NCI CA060553). Funding Information: This work was supported by grant I01CX000916 from the Department of Veterans Affairs, grants R01-CA121192, R01-CA77816 from the National Institutes of Health grants and by funds from the Vassilatos foundation. Publisher Copyright: Copyright: {\textcopyright} Kosciuczuk et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0).",

year = "2019",

doi = "10.18632/oncotarget.27388",

language = "English (US)",

volume = "10",

pages = "7112--7121",

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T1 - Inhibitory effects of SEL201 in acute myeloid leukemia

AU - Kosciuczuk, Ewa M.

AU - Kar, Aroop K.

AU - Blyth, Gavin T.

AU - Fischietti, Mariafausta

AU - Abedin, Sameem

AU - Mina, Alain A.

AU - Siliezar, Rebekah

AU - Rzymski, Tomasz

AU - Brzozka, Krzysztof

AU - Eklund, Elizabeth A.

AU - Beauchamp, Elspeth M.

AU - Eckerdt, Frank

AU - Saleiro, Diana

AU - Platanias, Leonidas C.

N1 - Funding Information: This work was supported by the Northwestern University – Flow Cytometry Core Facility supported by Cancer Center Support Grant (NCI CA060553). Funding Information: This work was supported by grant I01CX000916 from the Department of Veterans Affairs, grants R01-CA121192, R01-CA77816 from the National Institutes of Health grants and by funds from the Vassilatos foundation. Publisher Copyright: Copyright: © Kosciuczuk et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0).

PY - 2019

Y1 - 2019

N2 - MAPK interacting kinase (MNK), a downstream effector of mitogen-activated protein kinase (MAPK) pathways, activates eukaryotic translation initiation factor 4E (eIF4E) and plays a key role in the mRNA translation of mitogenic and antiapoptotic genes in acute myeloid leukemia (AML) cells. We examined the antileukemic properties of a novel MNK inhibitor, SEL201. Our studies provide evidence that SEL201 suppresses eIF4E phosphorylation on Ser209 in AML cell lines and in primary patient-derived AML cells. Such effects lead to growth inhibitory effects and leukemic cell apoptosis, as well as suppression of leukemic progenitor colony formation. Combination of SEL201 with 5'-azacytidine or rapamycin results in synergistic inhibition of AML cell growth. Collectively, these results suggest that SEL201 has significant antileukemic activity and further underscore the relevance of the MNK pathway in leukemogenesis.

AB - MAPK interacting kinase (MNK), a downstream effector of mitogen-activated protein kinase (MAPK) pathways, activates eukaryotic translation initiation factor 4E (eIF4E) and plays a key role in the mRNA translation of mitogenic and antiapoptotic genes in acute myeloid leukemia (AML) cells. We examined the antileukemic properties of a novel MNK inhibitor, SEL201. Our studies provide evidence that SEL201 suppresses eIF4E phosphorylation on Ser209 in AML cell lines and in primary patient-derived AML cells. Such effects lead to growth inhibitory effects and leukemic cell apoptosis, as well as suppression of leukemic progenitor colony formation. Combination of SEL201 with 5'-azacytidine or rapamycin results in synergistic inhibition of AML cell growth. Collectively, these results suggest that SEL201 has significant antileukemic activity and further underscore the relevance of the MNK pathway in leukemogenesis.

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ER -

Inhibitory effects of SEL201 in acute myeloid leukemia

Abstract

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