title: Ikaros 6 protects acute lymphoblastic leukemia cells against daunorubicin-induced apoptosis by activating the Akt-FoxO1 pathway.
abstract: Ikaros isoform 6 (Ik6) is associated with a poor prognosis for children with acute lymphoblastic leukemia (ALL). Our previous study demonstrated that overexpression of Ik6 enhances proliferation and chemoresistance of leukemia cells, with a possible underlying mechanism that involves antiapoptosis. In the present study, we investigated whether Ik6 protects against apoptosis by regulating the Akt-FoxO1 pathway. Bone marrow samples from children with ALL were collected and evaluated. In Ik6+patients, the Akt-FoxO1 pathway was activated such that expression of phosphorylated Akt and FoxO1 was significantly increased, but that of Bim and p27 decreased. In vitro experiments in this study were performed by using human ALL Nalm-6 cells that were stably transfected with Ik6 (Nalm-6/Ik6) or Sup-B15 and Ik6 shRNA (Sup-B15/Ik6 shRNA). Upon treatment with daunorubicin, Nalm-6/Ik6 cells exhibited a statistically significant reduction in apoptosis, with increased expression of p-Akt and p-FoxO1. In contrast, an increase in apoptosis with decreased expression of p-Akt and p-FoxO1 was observed in Sup-B15/Ik6 shRNA cells. This protection was dependent on activation of caspase-3 cleavage. By using an activator and an inhibitor of Akt or FoxO1, we demonstrated that Akt or FoxO1 activation had no effect on Ik6 expression. In conclusion, Ik6, the upstream factor of Akt-FoxO1 pathway, can protect ALL cells against daunorubicin-induced apoptosis and can potentially be explored as a therapeutic target in the treatment of patients with ALL.
authors.affiliation: Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Han
authors.affiliation: Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Runming
authors.initials: R
authors.lastname: Jin
authors.affiliation: Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Meiling
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Guo
authors.affiliation: Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China daisy_may@163.com.
authors.forename: Fen
authors.initials: F
authors.lastname: Zhou
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D002648:Child; D019610:Cytoprotection / Q000187:drug effects*; D003630:Daunorubicin / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D000071161:Forkhead Box Protein O1 / Q000378:metabolism*; D020868:Gene Silencing / Q000187:drug effects; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology; D006801:Humans; D051740:Ikaros Transcription Factor / Q000378:metabolism*; D008297:Male; D010766:Phosphorylation / Q000187:drug effects; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000473:pathology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D006575:Heterocyclic Compounds, 3-Ring; C586512:Ikaros 6 protein, human; C548887:MK 2206; D051740:Ikaros Transcription Factor; D051057:Proto-Oncogene Proteins c-akt; D003630:Daunorubicin
keywords: B lymphocyte; gene; signal transduction