YM155 potently kills acute lymphoblastic leukemia cells through activation of the DNA damage pathway

Bill Chang, Kara Johnson, Dorian LaTocha, Joelle S J Rowley, Jade Bryant, Russell Burke, Rebecca L. Smith, Marc Loriaux, Markus Müschen, Charles Mullighan, Brian Druker, Jeffrey Tyner

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Background: Novel-targeted therapies are in rapid development for the treatment of acute lymphoblastic leukemia (ALL) to overcome resistance and decrease toxicity. Survivin, a member of the inhibitor of apoptosis gene family and chromosome passenger complex, is critical in a variety of human cancers, including ALL. A well-established suppressor of survivin has been the small molecule, YM155. Reports are identifying other mechanisms of action for YM155. Therefore, we sought to investigate the mode of action and role of YM155 for therapeutic use in the context of ALL. Methods: Primary ALL samples and ALL cell lines were interrogated with YM155 to identify drug sensitivity. Ph+ALL harboring the BCR-ABL1 oncogene were tested for any interaction with YM155 and the multi-kinase inhibitor dasatinib. Representative ALL cell lines were tested to identify the response to YM155 using standard biochemical assays as well as RNA expression and phosphorylation arrays. Results: ALL samples exhibited significant sensitivity to YM155, and an additive response was observed with dasatinib in the setting of Ph+ALL. ALL cells were more sensitive to YM155 during S phase during DNA replication. YM155 activates the DNA damage pathway leading to phosphorylation of Chk2 and H2AX. Interestingly, screening of primary patient samples identified unique and exquisite YM155 sensitivity in some but not all ALL specimens. Conclusion: These results are the first to have screened a large number of primary patient leukemic samples to identify individual variations of response to YM155. Our studies further support that YM155 in ALL induces DNA damage leading to S phase arrest. Finally, only subsets of ALL have exquisite sensitivity to YM155 presumably through both suppression of survivin expression and activation of the DNA damage pathway underscoring its potential for therapeutic development.

Original languageEnglish (US)
Article number39
JournalJournal of Hematology and Oncology
Volume8
Issue number1
DOIs
StatePublished - Apr 22 2015

Fingerprint

Precursor Cell Lymphoblastic Leukemia-Lymphoma
DNA Damage
S Phase
Phosphorylation
Cell Line
Therapeutic Uses
DNA Replication
Oncogenes
Phosphotransferases
Therapeutics
Chromosomes
RNA
Apoptosis

Keywords

  • Acute lymphoblastic leukemia
  • DNA damage
  • YM155

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research
  • Molecular Biology

Cite this

YM155 potently kills acute lymphoblastic leukemia cells through activation of the DNA damage pathway. / Chang, Bill; Johnson, Kara; LaTocha, Dorian; Rowley, Joelle S J; Bryant, Jade; Burke, Russell; Smith, Rebecca L.; Loriaux, Marc; Müschen, Markus; Mullighan, Charles; Druker, Brian; Tyner, Jeffrey.

In: Journal of Hematology and Oncology, Vol. 8, No. 1, 39, 22.04.2015.

Research output: Contribution to journalArticle

Chang, Bill ; Johnson, Kara ; LaTocha, Dorian ; Rowley, Joelle S J ; Bryant, Jade ; Burke, Russell ; Smith, Rebecca L. ; Loriaux, Marc ; Müschen, Markus ; Mullighan, Charles ; Druker, Brian ; Tyner, Jeffrey. / YM155 potently kills acute lymphoblastic leukemia cells through activation of the DNA damage pathway. In: Journal of Hematology and Oncology. 2015 ; Vol. 8, No. 1.
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abstract = "Background: Novel-targeted therapies are in rapid development for the treatment of acute lymphoblastic leukemia (ALL) to overcome resistance and decrease toxicity. Survivin, a member of the inhibitor of apoptosis gene family and chromosome passenger complex, is critical in a variety of human cancers, including ALL. A well-established suppressor of survivin has been the small molecule, YM155. Reports are identifying other mechanisms of action for YM155. Therefore, we sought to investigate the mode of action and role of YM155 for therapeutic use in the context of ALL. Methods: Primary ALL samples and ALL cell lines were interrogated with YM155 to identify drug sensitivity. Ph+ALL harboring the BCR-ABL1 oncogene were tested for any interaction with YM155 and the multi-kinase inhibitor dasatinib. Representative ALL cell lines were tested to identify the response to YM155 using standard biochemical assays as well as RNA expression and phosphorylation arrays. Results: ALL samples exhibited significant sensitivity to YM155, and an additive response was observed with dasatinib in the setting of Ph+ALL. ALL cells were more sensitive to YM155 during S phase during DNA replication. YM155 activates the DNA damage pathway leading to phosphorylation of Chk2 and H2AX. Interestingly, screening of primary patient samples identified unique and exquisite YM155 sensitivity in some but not all ALL specimens. Conclusion: These results are the first to have screened a large number of primary patient leukemic samples to identify individual variations of response to YM155. Our studies further support that YM155 in ALL induces DNA damage leading to S phase arrest. Finally, only subsets of ALL have exquisite sensitivity to YM155 presumably through both suppression of survivin expression and activation of the DNA damage pathway underscoring its potential for therapeutic development.",
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AU - Johnson, Kara

AU - LaTocha, Dorian

AU - Rowley, Joelle S J

AU - Bryant, Jade

AU - Burke, Russell

AU - Smith, Rebecca L.

AU - Loriaux, Marc

AU - Müschen, Markus

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AU - Druker, Brian

AU - Tyner, Jeffrey

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AB - Background: Novel-targeted therapies are in rapid development for the treatment of acute lymphoblastic leukemia (ALL) to overcome resistance and decrease toxicity. Survivin, a member of the inhibitor of apoptosis gene family and chromosome passenger complex, is critical in a variety of human cancers, including ALL. A well-established suppressor of survivin has been the small molecule, YM155. Reports are identifying other mechanisms of action for YM155. Therefore, we sought to investigate the mode of action and role of YM155 for therapeutic use in the context of ALL. Methods: Primary ALL samples and ALL cell lines were interrogated with YM155 to identify drug sensitivity. Ph+ALL harboring the BCR-ABL1 oncogene were tested for any interaction with YM155 and the multi-kinase inhibitor dasatinib. Representative ALL cell lines were tested to identify the response to YM155 using standard biochemical assays as well as RNA expression and phosphorylation arrays. Results: ALL samples exhibited significant sensitivity to YM155, and an additive response was observed with dasatinib in the setting of Ph+ALL. ALL cells were more sensitive to YM155 during S phase during DNA replication. YM155 activates the DNA damage pathway leading to phosphorylation of Chk2 and H2AX. Interestingly, screening of primary patient samples identified unique and exquisite YM155 sensitivity in some but not all ALL specimens. Conclusion: These results are the first to have screened a large number of primary patient leukemic samples to identify individual variations of response to YM155. Our studies further support that YM155 in ALL induces DNA damage leading to S phase arrest. Finally, only subsets of ALL have exquisite sensitivity to YM155 presumably through both suppression of survivin expression and activation of the DNA damage pathway underscoring its potential for therapeutic development.

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