CDKN1A-mediated responsiveness of MLL-AF4-positive acute lymphoblastic leukemia to Aurora kinase-A inhibitors

Ya-Ping Chen, Hui Ju Lin, Chien-Hsu Chen, Ming Ying Tsai, Hsing Pang Hsieh, Jang-Yang Chang, Nai Feng Chen, Kung-Chao Chang, Wen Tsung Huang, Wu-Chou Su, Shu Ting Yang, Wen Chang Chang, Liang-Yi Hung, Tsai-Yun Chen

Research output: Contribution to journalArticle

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Abstract

Overexpression of Aurora kinases is largely observed in many cancers, including hematologic malignancies. In this study, we investigated the effects and molecular mechanisms of Aurora kinase inhibitors in acute lymphoblastic leukemia (ALL). Western blot analysis showed that both Aurora-A and Aurora-B are overexpressed in ALL cell lines and primary ALL cells. Both VE-465 and VX-680 effectively inhibited Aurora kinase activities in nine ALL cell lines, which exhibited different susceptibilities to the inhibitors. Cells sensitive to Aurora kinase inhibitors underwent apoptosis at an IC 50 of-10-30 nM and displayed a phenotype of Aurora-A inhibition, whereas cells resistant to Aurora kinase inhibitors (with an IC 50 more than 10 μM) accumulated polyploidy, which may have resulted from Aurora-B inhibition. Drug susceptibility of ALL cell lines was not correlated with the expression level or activation status of Aurora kinases. Interestingly, RS4;11 and MV4;11 cells, which contain the MLL-AF4 gene, were both sensitive to Aurora kinase-A inhibitors treatment. Complementary DNA (cDNA) microarray analysis suggested that CDKN1A might govern the drug responsiveness of ALL cell lines in a TP53-independent manner. Most importantly, primary ALL cells with MLL-AF4 and CDKN1A expression were sensitive to Aurora kinase inhibitors. Our study suggests CDKN1A could be a potential biomarker in determining the drug responsiveness of Aurora kinase inhibitors in ALL, particularly in MLL-AF4-positive patients. What's new? Aurora kinase overexpression is a phenomenon of many cancers, including hematologic malignancies, such as acute lymphoblastic leukemia (ALL). This study suggests that Aurora-A kinase inhibitors may have clinical utility in MLL-AF4-positive ALL and provides insight into the role of CDKN1A expression in governing ALL cell responsiveness to the drugs. CDKN1A acts in a TP53-independent manner and thereby serves as an indicator to determine drug responsiveness specifically in MLL-AF4-positive ALL cells.

Original languageEnglish
Pages (from-to)751-762
Number of pages12
JournalInternational Journal of Cancer
Volume135
Issue number3
DOIs
Publication statusPublished - 2014 Aug 1

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Aurora Kinase A
Aurora Kinases
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Cell Line
Pharmaceutical Preparations
Hematologic Neoplasms
Polyploidy
Microarray Analysis
Oligonucleotide Array Sequence Analysis

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Chen, Ya-Ping ; Lin, Hui Ju ; Chen, Chien-Hsu ; Tsai, Ming Ying ; Hsieh, Hsing Pang ; Chang, Jang-Yang ; Chen, Nai Feng ; Chang, Kung-Chao ; Huang, Wen Tsung ; Su, Wu-Chou ; Yang, Shu Ting ; Chang, Wen Chang ; Hung, Liang-Yi ; Chen, Tsai-Yun. / CDKN1A-mediated responsiveness of MLL-AF4-positive acute lymphoblastic leukemia to Aurora kinase-A inhibitors. In: International Journal of Cancer. 2014 ; Vol. 135, No. 3. pp. 751-762.
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abstract = "Overexpression of Aurora kinases is largely observed in many cancers, including hematologic malignancies. In this study, we investigated the effects and molecular mechanisms of Aurora kinase inhibitors in acute lymphoblastic leukemia (ALL). Western blot analysis showed that both Aurora-A and Aurora-B are overexpressed in ALL cell lines and primary ALL cells. Both VE-465 and VX-680 effectively inhibited Aurora kinase activities in nine ALL cell lines, which exhibited different susceptibilities to the inhibitors. Cells sensitive to Aurora kinase inhibitors underwent apoptosis at an IC 50 of-10-30 nM and displayed a phenotype of Aurora-A inhibition, whereas cells resistant to Aurora kinase inhibitors (with an IC 50 more than 10 μM) accumulated polyploidy, which may have resulted from Aurora-B inhibition. Drug susceptibility of ALL cell lines was not correlated with the expression level or activation status of Aurora kinases. Interestingly, RS4;11 and MV4;11 cells, which contain the MLL-AF4 gene, were both sensitive to Aurora kinase-A inhibitors treatment. Complementary DNA (cDNA) microarray analysis suggested that CDKN1A might govern the drug responsiveness of ALL cell lines in a TP53-independent manner. Most importantly, primary ALL cells with MLL-AF4 and CDKN1A expression were sensitive to Aurora kinase inhibitors. Our study suggests CDKN1A could be a potential biomarker in determining the drug responsiveness of Aurora kinase inhibitors in ALL, particularly in MLL-AF4-positive patients. What's new? Aurora kinase overexpression is a phenomenon of many cancers, including hematologic malignancies, such as acute lymphoblastic leukemia (ALL). This study suggests that Aurora-A kinase inhibitors may have clinical utility in MLL-AF4-positive ALL and provides insight into the role of CDKN1A expression in governing ALL cell responsiveness to the drugs. CDKN1A acts in a TP53-independent manner and thereby serves as an indicator to determine drug responsiveness specifically in MLL-AF4-positive ALL cells.",
author = "Ya-Ping Chen and Lin, {Hui Ju} and Chien-Hsu Chen and Tsai, {Ming Ying} and Hsieh, {Hsing Pang} and Jang-Yang Chang and Chen, {Nai Feng} and Kung-Chao Chang and Huang, {Wen Tsung} and Wu-Chou Su and Yang, {Shu Ting} and Chang, {Wen Chang} and Liang-Yi Hung and Tsai-Yun Chen",
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CDKN1A-mediated responsiveness of MLL-AF4-positive acute lymphoblastic leukemia to Aurora kinase-A inhibitors. / Chen, Ya-Ping; Lin, Hui Ju; Chen, Chien-Hsu; Tsai, Ming Ying; Hsieh, Hsing Pang; Chang, Jang-Yang; Chen, Nai Feng; Chang, Kung-Chao; Huang, Wen Tsung; Su, Wu-Chou; Yang, Shu Ting; Chang, Wen Chang; Hung, Liang-Yi; Chen, Tsai-Yun.

In: International Journal of Cancer, Vol. 135, No. 3, 01.08.2014, p. 751-762.

Research output: Contribution to journalArticle

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T1 - CDKN1A-mediated responsiveness of MLL-AF4-positive acute lymphoblastic leukemia to Aurora kinase-A inhibitors

AU - Chen, Ya-Ping

AU - Lin, Hui Ju

AU - Chen, Chien-Hsu

AU - Tsai, Ming Ying

AU - Hsieh, Hsing Pang

AU - Chang, Jang-Yang

AU - Chen, Nai Feng

AU - Chang, Kung-Chao

AU - Huang, Wen Tsung

AU - Su, Wu-Chou

AU - Yang, Shu Ting

AU - Chang, Wen Chang

AU - Hung, Liang-Yi

AU - Chen, Tsai-Yun

PY - 2014/8/1

Y1 - 2014/8/1

N2 - Overexpression of Aurora kinases is largely observed in many cancers, including hematologic malignancies. In this study, we investigated the effects and molecular mechanisms of Aurora kinase inhibitors in acute lymphoblastic leukemia (ALL). Western blot analysis showed that both Aurora-A and Aurora-B are overexpressed in ALL cell lines and primary ALL cells. Both VE-465 and VX-680 effectively inhibited Aurora kinase activities in nine ALL cell lines, which exhibited different susceptibilities to the inhibitors. Cells sensitive to Aurora kinase inhibitors underwent apoptosis at an IC 50 of-10-30 nM and displayed a phenotype of Aurora-A inhibition, whereas cells resistant to Aurora kinase inhibitors (with an IC 50 more than 10 μM) accumulated polyploidy, which may have resulted from Aurora-B inhibition. Drug susceptibility of ALL cell lines was not correlated with the expression level or activation status of Aurora kinases. Interestingly, RS4;11 and MV4;11 cells, which contain the MLL-AF4 gene, were both sensitive to Aurora kinase-A inhibitors treatment. Complementary DNA (cDNA) microarray analysis suggested that CDKN1A might govern the drug responsiveness of ALL cell lines in a TP53-independent manner. Most importantly, primary ALL cells with MLL-AF4 and CDKN1A expression were sensitive to Aurora kinase inhibitors. Our study suggests CDKN1A could be a potential biomarker in determining the drug responsiveness of Aurora kinase inhibitors in ALL, particularly in MLL-AF4-positive patients. What's new? Aurora kinase overexpression is a phenomenon of many cancers, including hematologic malignancies, such as acute lymphoblastic leukemia (ALL). This study suggests that Aurora-A kinase inhibitors may have clinical utility in MLL-AF4-positive ALL and provides insight into the role of CDKN1A expression in governing ALL cell responsiveness to the drugs. CDKN1A acts in a TP53-independent manner and thereby serves as an indicator to determine drug responsiveness specifically in MLL-AF4-positive ALL cells.

AB - Overexpression of Aurora kinases is largely observed in many cancers, including hematologic malignancies. In this study, we investigated the effects and molecular mechanisms of Aurora kinase inhibitors in acute lymphoblastic leukemia (ALL). Western blot analysis showed that both Aurora-A and Aurora-B are overexpressed in ALL cell lines and primary ALL cells. Both VE-465 and VX-680 effectively inhibited Aurora kinase activities in nine ALL cell lines, which exhibited different susceptibilities to the inhibitors. Cells sensitive to Aurora kinase inhibitors underwent apoptosis at an IC 50 of-10-30 nM and displayed a phenotype of Aurora-A inhibition, whereas cells resistant to Aurora kinase inhibitors (with an IC 50 more than 10 μM) accumulated polyploidy, which may have resulted from Aurora-B inhibition. Drug susceptibility of ALL cell lines was not correlated with the expression level or activation status of Aurora kinases. Interestingly, RS4;11 and MV4;11 cells, which contain the MLL-AF4 gene, were both sensitive to Aurora kinase-A inhibitors treatment. Complementary DNA (cDNA) microarray analysis suggested that CDKN1A might govern the drug responsiveness of ALL cell lines in a TP53-independent manner. Most importantly, primary ALL cells with MLL-AF4 and CDKN1A expression were sensitive to Aurora kinase inhibitors. Our study suggests CDKN1A could be a potential biomarker in determining the drug responsiveness of Aurora kinase inhibitors in ALL, particularly in MLL-AF4-positive patients. What's new? Aurora kinase overexpression is a phenomenon of many cancers, including hematologic malignancies, such as acute lymphoblastic leukemia (ALL). This study suggests that Aurora-A kinase inhibitors may have clinical utility in MLL-AF4-positive ALL and provides insight into the role of CDKN1A expression in governing ALL cell responsiveness to the drugs. CDKN1A acts in a TP53-independent manner and thereby serves as an indicator to determine drug responsiveness specifically in MLL-AF4-positive ALL cells.

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