title: Therapeutic polo-like kinase 1 inhibition results in mitotic arrest and subsequent cell death of blasts in the bone marrow of AML patients and has similar effects in non-neoplastic cell lines.
abstract: Polo-like kinase 1 (PLK1) is an important regulator of the cell cycle and is overexpressed in various solid and hematological malignancies. Small molecule inhibitors targeting PLK1, such as BI2536 or BI6727 (Volasertib) are a promising therapeutic approach in such malignancies. Here, we show a loss of specifically localized PLK1 in AML blasts in vivo, accompanied by mitotic arrest with transition into apoptosis, in bone marrow biopsies of AML patients after treatment with BI2536. We verify these results in live cell imaging experiments with the AML cell line HL-60, and demonstrate that non-neoplastic, immortalized lymphoblastoid cells are also sensitive to PLK1 inhibition. It is demonstrated that normal granulopoietic precursors have similar PLK1 expression levels as leukemic blasts. These results are in line with the adverse effects of PLK1 inhibition and underline the great potential of PLK1 inhibitors in the treatment of AML.
authors.affiliation: Institute of Clinical Pathology, Department of Pathology, University Medical Center, Breisacher Str. 115a, 79106 Freiburg, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Münch
authors.affiliation: Institute of Clinical Pathology, Department of Pathology, University Medical Center, Breisacher Str. 115a, 79106 Freiburg, Germany.
authors.forename: Diana
authors.initials: D
authors.lastname: Dragoi
authors.affiliation: Institute of Clinical Pathology, Department of Pathology, University Medical Center, Breisacher Str. 115a, 79106 Freiburg, Germany.
authors.forename: Anna-Verena
authors.initials: AV
authors.lastname: Frey
authors.affiliation: Institute of Clinical Pathology, Department of Pathology, University Medical Center, Breisacher Str. 115a, 79106 Freiburg, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Thurig
authors.affiliation: Department of Hematology and Oncology, University Medical Center, Hugstetter Str. 55, 79106 Freiburg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Lübbert
authors.affiliation: Department of Hematology and Oncology, University Medical Center, Hugstetter Str. 55, 79106 Freiburg, Germany.
authors.forename: Ralph
authors.initials: R
authors.lastname: Wäsch
authors.affiliation: Institute of Medical Biometry and Medical Informatics, University Medical Center, Stefan-Meier-Str. 26, 79104 Freiburg, Germany.
authors.forename: Lioudmila
authors.initials: L
authors.lastname: Bogatyreva
authors.affiliation: Institute of Medical Biometry and Medical Informatics, University Medical Center, Stefan-Meier-Str. 26, 79104 Freiburg, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Hauschke
authors.affiliation: Institute of Clinical Pathology, Department of Pathology, University Medical Center, Breisacher Str. 115a, 79106 Freiburg, Germany; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany; BIOSS Centre for Biological Signalling Studies, University of Freiburg, Germany.
authors.forename: Silke
authors.initials: S
authors.lastname: Lassmann
authors.affiliation: Institute of Clinical Pathology, Department of Pathology, University Medical Center, Breisacher Str. 115a, 79106 Freiburg, Germany; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Werner
authors.affiliation: Institute of Clinical Pathology, Department of Pathology, University Medical Center, Breisacher Str. 115a, 79106 Freiburg, Germany. Electronic address: annette.may@uniklinik-freiburg.de.
authors.forename: Annette M
authors.initials: AM
authors.lastname: May
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D050256:Antimitotic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001752:Blast Crisis / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D015153:Blotting, Western; D001853:Bone Marrow / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology*; D008297:Male; D008938:Mitosis / Q000187:drug effects*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011621:Pteridines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D000097869:Polo-Like Kinase 1
chemical_list: D050256:Antimitotic Agents; D018797:Cell Cycle Proteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D011621:Pteridines; D012333:RNA, Messenger; D000097869:Polo-Like Kinase 1; C518477:BI 2536; C541363:BI 6727
keywords: AML; BI2536; BI6727; Bone marrow biopsy; Hematopoietic cells; Live cell imaging; PLK1 inhibition; Volasertib