title: Suppression of APC/CCdh1 has subtype specific biological effects in acute myeloid leukemia.
abstract: The E3 ubiquitin ligase and tumor suppressor APC/CCdh1 is crucial for cell cycle progression, development and differentiation in many cell types. However, little is known about the role of Cdh1 in hematopoiesis. Here we analyzed Cdh1 expression and function in malignant hematopoiesis. We found a significant decrease of Cdh1 in primary acute myeloid leukemia (AML) blasts compared to normal CD34+ cells. Thus, according to its important role in connecting cell cycle exit and differentiation, decreased expression of Cdh1 may be a mechanism contributing to the differentiation block in leukemogenesis. Indeed, knockdown (kd) of Cdh1 in HL-60 cell line (AML with maturation, FAB M2) led to less differentiated cells and a delay in PMA-induced differentiation. Acute promyelocytic leukemia (APL, FAB M3) is an AML subtype which is highly vulnerable to differentiation therapy with all-trans retinoic acid (ATRA). Accordingly, we found that APL is resistant to a Cdh1-kd mediated differentiation block. However, further depletion of Cdh1 in APL significantly reduced viability of leukemia cells upon ATRA-induced differentiation. Thus, low Cdh1 expression may be important in AML biology by contributing to the differentiation block and response to therapy depending on differences in the microenvironment and the additional genetic background.
authors.affiliation: Department of Hematology, Oncology and Stem Cell Transplantation, University Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.|Faculty of Biology, University of Freiburg, Freiburg, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Ewerth
authors.affiliation: Department of Hematology, Oncology and Stem Cell Transplantation, University Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Schmidts
authors.affiliation: Department of Hematology, Oncology and Stem Cell Transplantation, University Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.|Present address: Department of Cardiology and Angiology II, University Heart Center Freiburg - Bad Krozingen, Faculty of Medicine, University of Freiburg, Bad Krozingen, Germany.
authors.forename: Manuel
authors.initials: M
authors.lastname: Hein
authors.affiliation: Department of Hematology, Oncology and Stem Cell Transplantation, University Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
authors.forename: Dominik
authors.initials: D
authors.lastname: Schnerch
authors.affiliation: Department of Hematology, Oncology and Stem Cell Transplantation, University Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.|Present address: Center for Biological Systems Analysis, University of Freiburg, Freiburg, Germany.
authors.forename: Arunas
authors.initials: A
authors.lastname: Kvainickas
authors.affiliation: Department of Hematology, Oncology and Stem Cell Transplantation, University Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Greil
authors.affiliation: Department of Hematology, Oncology and Stem Cell Transplantation, University Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
authors.forename: Justus
authors.initials: J
authors.lastname: Duyster
authors.affiliation: Department of Hematology, Oncology and Stem Cell Transplantation, University Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
authors.forename: Monika
authors.initials: M
authors.lastname: Engelhardt
authors.affiliation: Department of Hematology, Oncology and Stem Cell Transplantation, University Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
authors.forename: Ralph
authors.initials: R
authors.lastname: Wäsch
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015703:Antigens, CD; D015820:Cadherins / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D005260:Female; D055785:Gene Knockdown Techniques; D018922:HL-60 Cells; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015473:Leukemia, Promyelocytic, Acute / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014212:Tretinoin / Q000494:pharmacology; D055815:Young Adult
chemical_list: D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins; D014212:Tretinoin; D013755:Tetradecanoylphorbol Acetate
keywords: Cdh1; acute myeloid leukemia; anaphase-promoting complex; differentiation; ubiquitin-ligase