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 journalArticlepeer-review

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

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

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