title: Maintenance of leukemia-initiating cells is regulated by the CDK inhibitor Inca1.
abstract: Functional differences between healthy progenitor and cancer initiating cells may provide unique opportunities for targeted therapy approaches. Hematopoietic stem cells are tightly controlled by a network of CDK inhibitors that govern proliferation and prevent stem cell exhaustion. Loss of Inca1 led to an increased number of short-term hematopoietic stem cells in older mice, but Inca1 seems largely dispensable for normal hematopoiesis. On the other hand, Inca1-deficiency enhanced cell cycling upon cytotoxic stress and accelerated bone marrow exhaustion. Moreover, AML1-ETO9a-induced proliferation was not sustained in Inca1-deficient cells in vivo. As a consequence, leukemia induction and leukemia maintenance were severely impaired in Inca1-/- bone marrow cells. The re-initiation of leukemia was also significantly inhibited in absence of Inca1-/- in MLL-AF9- and c-myc/BCL2-positive leukemia mouse models. These findings indicate distinct functional properties of Inca1 in normal hematopoietic cells compared to leukemia initiating cells. Such functional differences might be used to design specific therapy approaches in leukemia.
authors.affiliation: Department of Medicine A, Hematology/Oncology, University of Muenster, 48129 Muenster, Germany; Interdisciplinary Center for Clinical Research (IZKF), University of Muenster, 48129 Muenster, Germany.
authors.forename: Nicole
authors.initials: N
authors.lastname: Bäumer
authors.affiliation: Department of Medicine A, Hematology/Oncology, University of Muenster, 48129 Muenster, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Bäumer
authors.affiliation: Department of Medicine A, Hematology/Oncology, University of Muenster, 48129 Muenster, Germany; Max-Planck-Institute for Molecular Biomedicine, Department of Tissue Morphogenesis, and University of Muenster, Faculty of Medicine, Muenster, 48129 Muenster, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Berkenfeld
authors.affiliation: Max-Planck-Institute for Molecular Biomedicine, Department of Tissue Morphogenesis, and University of Muenster, Faculty of Medicine, Muenster, 48129 Muenster, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Stehling
authors.affiliation: Institute for Pathology, Clinical Center Fulda, 36043 Fulda, Germany.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Köhler
authors.affiliation: Department of Medicine A, Hematology/Oncology, University of Muenster, 48129 Muenster, Germany.
authors.forename: Wolfgang E
authors.initials: WE
authors.lastname: Berdel
authors.affiliation: Department of Medicine A, Hematology/Oncology, University of Muenster, 48129 Muenster, Germany; Interdisciplinary Center for Clinical Research (IZKF), University of Muenster, 48129 Muenster, Germany; Dept. of Medicine IV, Hematology and Oncology, University of Halle, 06120 Halle, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Müller-Tidow
authors.affiliation: Department of Medicine A, Hematology/Oncology, University of Muenster, 48129 Muenster, Germany; Interdisciplinary Center for Clinical Research (IZKF), University of Muenster, 48129 Muenster, Germany; Dept. of Medicine IV, Hematology and Oncology, University of Halle, 06120 Halle, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Tschanter
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002453:Cell Cycle; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D007942:Leukemia, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D014411:Neoplastic Stem Cells / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; C000603586:Inca1 protein, mouse