title: 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.
authors.affiliation: Department of Hematology and Respiratory Medicine, Kochi Medical School, Kochi University, Kochi, Japan; Department of Immunology, Kochi Medical School, Kochi University, Kochi, Japan.
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
authors.forename: Takayuki
authors.initials: T
authors.lastname: Ikezoe
authors.forename: Chie
authors.initials: C
authors.lastname: Nishioka
authors.forename: Atsuya
authors.initials: A
authors.lastname: Nobumoto
authors.forename: Keiko
authors.initials: K
authors.lastname: Udaka
authors.forename: Akihito
authors.initials: A
authors.lastname: Yokoyama
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000235:genetics; D000818:Animals; D018952:Antigens, CD34 / Q000235:genetics; D017209:Apoptosis / Q000187:drug effects; D064096:Aurora Kinase A / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D001381:Azepines / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D051379:Mice; D058990:Molecular Targeted Therapy; D011743:Pyrimidines / Q000494:pharmacology
chemical_list: D018952:Antigens, CD34; D001381:Azepines; C550258:MLN 8237; D011743:Pyrimidines; C576917:AURKA protein, human; D064096:Aurora Kinase A; D051997:ADP-ribosyl Cyclase 1
keywords: AURKA; CD34+/CD38− AML cells; MLN8237; apoptosis