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 language | English (US) |
|---|---|
| Pages (from-to) | 1777-1789 |
| Number of pages | 13 |
| Journal | Blood |
| Volume | 124 |
| Issue number | 11 |
| DOIs | |
| State | Published - 2014 |
| Externally published | Yes |
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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 journal › Article
}
TY - JOUR
T1 - PIM inhibitors target CD25-positive AML cells through concomitant suppression of STAT5 activation and degradation of MYC oncogene.
AU - Guo, Zhuyan
AU - Wang, Anlai
AU - Zhang, Weidong
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
Y1 - 2014
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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84908615329&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84908615329&partnerID=8YFLogxK
U2 - 10.1182/blood-2014-01-551234
DO - 10.1182/blood-2014-01-551234
M3 - Article
C2 - 25006129
AN - SCOPUS:84908615329
VL - 124
SP - 1777
EP - 1789
JO - Blood
JF - Blood
SN - 0006-4971
IS - 11
ER -