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CD34⁺/CD38⁻ acute myelogenous leukemia cells aberrantly express Aurora kinase A.

Abstract
We previously showed that Aurora kinase A (AURKA) is aberrantly expressed in acute myelogenous leukemia (AML) cells when compared to bone marrow mononuclear cells isolated from healthy volunteers. We have also shown that CD34(+) /CD38(-) AML cells, one of compartments enriched for leukemia stem cells in most leukemia subgroups, were relatively resistant to cytarabine-mediated growth inhibition when compared to their CD34(+) /CD38(+) counterparts. Our study attempted to identify therapeutic targets in CD34(+) /CD38(-) AML cells and found that CD34(+) /CD38(-) AML cells isolated from patients (n = 26) expressed larger amounts of AURKA than their CD34(+) /CD38(+) counterparts and CD34(+) normal hematopoietic stem/progenitor cells isolated from healthy volunteers (n = 6), as measured by real-time reverse-transcriptase polymerase chain reaction. Blockade of AURKA by the specific inhibitor MLN8237 or a short hairpin RNA (shRNA) against AURKA significantly inhibited proliferation, impaired self-renewal capability and induced apoptosis of CD34(+) /CD38(-) AML cells, in association with modulation of levels of Bcl-2 family member proteins. Importantly, inhibition of AURKA in CD34(+) /CD38(-) AML cells by MLN8237 or an shRNA significantly impaired engraftment of these cells in severely immunocompromised mice and appeared to prolong their survival. These results suggest that AURKA is a promising molecular target to eliminate chemotherapy-resistant CD34(+) /CD38(-) AML cells.
AuthorsJing Yang, Takayuki Ikezoe, Chie Nishioka, Atsuya Nobumoto, Keiko Udaka, Akihito Yokoyama
JournalInternational journal of cancer. Journal international du cancer (Int J Cancer) Vol. 133 Issue 11 Pg. 2706-19 (Dec 1 2013) ISSN: 1097-0215 [Electronic] United States
PMID23686525 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2013 UICC.
Chemical References
  • Antigens, CD34
  • Azepines
  • MLN 8237
  • Pyrimidines
  • AURKA protein, human
  • Aurora Kinase A
  • Antigens, CD38
Topics
  • Animals
  • Antigens, CD34 (genetics)
  • Antigens, CD38 (genetics)
  • Apoptosis (drug effects)
  • Aurora Kinase A (antagonists & inhibitors, biosynthesis, genetics)
  • Azepines (pharmacology)
  • Cell Line, Tumor
  • Cell Proliferation
  • Gene Expression Regulation, Neoplastic (drug effects, genetics)
  • Humans
  • Leukemia, Myeloid, Acute (drug therapy, genetics, pathology)
  • Mice
  • Molecular Targeted Therapy
  • Pyrimidines (pharmacology)

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