title: HOXA10 expression induced by Abl kinase inhibitors enhanced apoptosis through PI3K pathway in CML cells.
abstract: Chronic myelogenous leukemia is characterized by the reciprocal chromosomal translocation (9;22), which generates a novel fusion gene, BCR-ABL. Bcr-Abl-expressing leukemia cells are highly resistant to apoptosis. Imatinib an Abl kinase inhibitor, is a highly effective agent for patients with CML. However, a small percentage of these patients and most advanced-phase patients relapse on imatinib therapy. It is poorly understood whether the Abl kinase inhibitors are able to eradicate CML progenitor or stem cells. In this study, we investigated the role of HOXA10 in CML cell lines and the hematopoietic progenitor cells derived from CML patients, and whether the regulation of HOXA10 eradicates Bcr-Abl(+) hematopoietic stem/progenitor cells. The Abl kinase inhibitors and PI3K inhibitor, LY294002, induced the expression of HOXA10, and it enhanced apoptosis in CML cells. Moreover, the reduction of HOXA10 expression by siRNA in CML cells inhibited apoptosis by treatment with the Abl kinase inhibitors and LY294002. These results revealed that HOXA10 had an important role in induction of apoptosis by the Abl kinase inhibitors in CML cells. Finally, we showed that the inhibition of HOXA10 expression by siRNA increased the numbers of CFU-GEMM, BFU-E, and CFU-GM when the cells were treated with the combination of BMS354825 and LY294002 compared to control cells, and HOXA10 played a critical role in the committed colony-formation in CML. This study shows for the first time that the Abl kinase inhibitor and LY294002 induced HOXA10, and HOXA10 had an important role in apoptosis or cell growth inhibition in CML cells in vitro.
authors.affiliation: Department of Internal Medicine III, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu city, Shizuoka 431-3192, Japan.
authors.forename: Yuya
authors.initials: Y
authors.lastname: Sugimoto
authors.forename: Satoki
authors.initials: S
authors.lastname: Nakamura
authors.forename: Keiji
authors.initials: K
authors.lastname: Okinaka
authors.forename: Isao
authors.initials: I
authors.lastname: Hirano
authors.forename: Takaaki
authors.initials: T
authors.lastname: Ono
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Shigeno
authors.forename: Kaori
authors.initials: K
authors.lastname: Shinjo
authors.forename: Kazunori
authors.initials: K
authors.lastname: Ohnishi
mesh_terms: D000328:Adult; D017209:Apoptosis / Q000187:drug effects*; D001549:Benzamides; D015153:Blotting, Western; D001853:Bone Marrow; D016022:Case-Control Studies; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D003114:Colony-Forming Units Assay; D017931:DNA Primers; D000069439:Dasatinib; D005260:Female; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000187:drug effects; D000080905:Homeobox A10 Proteins; D018398:Homeodomain Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D000068877:Imatinib Mesylate; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010879:Piperazines; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013844:Thiazoles / Q000494:pharmacology; D014162:Transfection
chemical_list: D001549:Benzamides; D002867:Chromones; D017931:DNA Primers; D000069439:Dasatinib; D000080905:Homeobox A10 Proteins; D018398:Homeodomain Proteins; D000068877:Imatinib Mesylate; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D016315:Proto-Oncogene Proteins c-abl; D011743:Pyrimidines; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D013844:Thiazoles; C069634:HOXA10 protein, human; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one