PIM inhibitors target CD25-positive AML cells through concomitant suppression of STAT5 activation and degradation of MYC oncogene.

Zhuyan Guo, Anlai Wang, Weidong Zhang, Mikhail Levit, Qiang Gao, Claude Barberis, Michel Tabart, Jingxin Zhang, Dietmar Hoffmann, Dmitri Wiederschain, Jennifer Rocnik, Fangxian Sun, Josh Murtie, Christoph Lengauer, Stefan Gross, Bailin Zhang, Hong Cheng, Vinod Patel, Laurent Schio, Francisco AdrianMarion Dorsch, Carlos Garcia-Echeverria, Shih Min A Huang

Research output: Contribution to journalArticle

Abstract

Postchemotherapy relapse presents a major unmet medical need in acute myeloid leukemia (AML), where treatment options are limited. CD25 is a leukemic stem cell marker and a conspicuous prognostic marker for overall/relapse-free survival in AML. Rare occurrence of genetic alterations among PIM family members imposes a substantial hurdle in formulating a compelling patient stratification strategy for the clinical development of selective PIM inhibitors in cancer. Here we show that CD25, a bona fide STAT5 regulated gene, is a mechanistically relevant predictive biomarker for sensitivity to PIM kinase inhibitors. Alone or in combination with tyrosine kinase inhibitors, PIM inhibitors can suppress STAT5 activation and significantly shorten the half-life of MYC to achieve substantial growth inhibition of high CD25-expressing AML cells. Our results highlight the importance of STAT5 and MYC in rendering cancer cells sensitive to PIM inhibitors. Because the presence of a CD25-positive subpopulation in leukemic blasts correlates with poor overall or relapse-free survival, our data suggest that a combination of PIM inhibitors with chemotherapy and tyrosine kinase inhibitors could improve long-term therapeutic outcomes in CD25-positive AML.

Original languageEnglish (US)
Pages (from-to)1777-1789
Number of pages13
JournalBlood
Volume124
Issue number11
DOIs
StatePublished - 2014
Externally publishedYes

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Myeloid Cells
Oncogenes
Acute Myeloid Leukemia
Protein-Tyrosine Kinases
Chemical activation
Degradation
Chemotherapy
Biomarkers
Stem cells
Recurrence
Phosphotransferases
Genes
Cells
Survival
Half-Life
Neoplasms
Stem Cells
Drug Therapy
Therapeutics
Growth

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

PIM inhibitors target CD25-positive AML cells through concomitant suppression of STAT5 activation and degradation of MYC oncogene. / Guo, Zhuyan; Wang, Anlai; Zhang, Weidong; Levit, Mikhail; Gao, Qiang; Barberis, Claude; Tabart, Michel; Zhang, Jingxin; Hoffmann, Dietmar; Wiederschain, Dmitri; Rocnik, Jennifer; Sun, Fangxian; Murtie, Josh; Lengauer, Christoph; Gross, Stefan; Zhang, Bailin; Cheng, Hong; Patel, Vinod; Schio, Laurent; Adrian, Francisco; Dorsch, Marion; Garcia-Echeverria, Carlos; Huang, Shih Min A.

In: Blood, Vol. 124, No. 11, 2014, p. 1777-1789.

Research output: Contribution to journalArticle

Guo, Z, Wang, A, Zhang, W, Levit, M, Gao, Q, Barberis, C, Tabart, M, Zhang, J, Hoffmann, D, Wiederschain, D, Rocnik, J, Sun, F, Murtie, J, Lengauer, C, Gross, S, Zhang, B, Cheng, H, Patel, V, Schio, L, Adrian, F, Dorsch, M, Garcia-Echeverria, C & Huang, SMA 2014, 'PIM inhibitors target CD25-positive AML cells through concomitant suppression of STAT5 activation and degradation of MYC oncogene.', Blood, vol. 124, no. 11, pp. 1777-1789. https://doi.org/10.1182/blood-2014-01-551234
Guo, Zhuyan ; Wang, Anlai ; Zhang, Weidong ; Levit, Mikhail ; Gao, Qiang ; Barberis, Claude ; Tabart, Michel ; Zhang, Jingxin ; Hoffmann, Dietmar ; Wiederschain, Dmitri ; Rocnik, Jennifer ; Sun, Fangxian ; Murtie, Josh ; Lengauer, Christoph ; Gross, Stefan ; Zhang, Bailin ; Cheng, Hong ; Patel, Vinod ; Schio, Laurent ; Adrian, Francisco ; Dorsch, Marion ; Garcia-Echeverria, Carlos ; Huang, Shih Min A. / PIM inhibitors target CD25-positive AML cells through concomitant suppression of STAT5 activation and degradation of MYC oncogene. In: Blood. 2014 ; Vol. 124, No. 11. pp. 1777-1789.
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abstract = "Postchemotherapy relapse presents a major unmet medical need in acute myeloid leukemia (AML), where treatment options are limited. CD25 is a leukemic stem cell marker and a conspicuous prognostic marker for overall/relapse-free survival in AML. Rare occurrence of genetic alterations among PIM family members imposes a substantial hurdle in formulating a compelling patient stratification strategy for the clinical development of selective PIM inhibitors in cancer. Here we show that CD25, a bona fide STAT5 regulated gene, is a mechanistically relevant predictive biomarker for sensitivity to PIM kinase inhibitors. Alone or in combination with tyrosine kinase inhibitors, PIM inhibitors can suppress STAT5 activation and significantly shorten the half-life of MYC to achieve substantial growth inhibition of high CD25-expressing AML cells. Our results highlight the importance of STAT5 and MYC in rendering cancer cells sensitive to PIM inhibitors. Because the presence of a CD25-positive subpopulation in leukemic blasts correlates with poor overall or relapse-free survival, our data suggest that a combination of PIM inhibitors with chemotherapy and tyrosine kinase inhibitors could improve long-term therapeutic outcomes in CD25-positive AML.",
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AU - Levit, Mikhail

AU - Gao, Qiang

AU - Barberis, Claude

AU - Tabart, Michel

AU - Zhang, Jingxin

AU - Hoffmann, Dietmar

AU - Wiederschain, Dmitri

AU - Rocnik, Jennifer

AU - Sun, Fangxian

AU - Murtie, Josh

AU - Lengauer, Christoph

AU - Gross, Stefan

AU - Zhang, Bailin

AU - Cheng, Hong

AU - Patel, Vinod

AU - Schio, Laurent

AU - Adrian, Francisco

AU - Dorsch, Marion

AU - Garcia-Echeverria, Carlos

AU - Huang, Shih Min A

PY - 2014

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N2 - Postchemotherapy relapse presents a major unmet medical need in acute myeloid leukemia (AML), where treatment options are limited. CD25 is a leukemic stem cell marker and a conspicuous prognostic marker for overall/relapse-free survival in AML. Rare occurrence of genetic alterations among PIM family members imposes a substantial hurdle in formulating a compelling patient stratification strategy for the clinical development of selective PIM inhibitors in cancer. Here we show that CD25, a bona fide STAT5 regulated gene, is a mechanistically relevant predictive biomarker for sensitivity to PIM kinase inhibitors. Alone or in combination with tyrosine kinase inhibitors, PIM inhibitors can suppress STAT5 activation and significantly shorten the half-life of MYC to achieve substantial growth inhibition of high CD25-expressing AML cells. Our results highlight the importance of STAT5 and MYC in rendering cancer cells sensitive to PIM inhibitors. Because the presence of a CD25-positive subpopulation in leukemic blasts correlates with poor overall or relapse-free survival, our data suggest that a combination of PIM inhibitors with chemotherapy and tyrosine kinase inhibitors could improve long-term therapeutic outcomes in CD25-positive AML.

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