title: ICL-induced miR139-3p and miR199a-3p have opposite roles in hematopoietic cell expansion and leukemic transformation.
abstract: Interstrand crosslinks (ICLs) are toxic DNA lesions that cause severe genomic damage during replication, especially in Fanconi anemia pathway-deficient cells. This results in progressive bone marrow failure and predisposes to acute myeloid leukemia (AML). The molecular mechanisms responsible for these defects are largely unknown. Using Ercc1-deficient mice, we show that Trp53 is responsible for ICL-induced bone marrow failure and that loss of Trp53 is leukemogenic in this model. In addition, Ercc1-deficient myeloid progenitors gain elevated levels of miR-139-3p and miR-199a-3p with age. These microRNAs exert opposite effects on hematopoiesis. Ectopic expression of miR-139-3p strongly inhibited proliferation of myeloid progenitors, whereas inhibition of miR-139-3p activity restored defective proliferation of Ercc1-deficient progenitors. Conversely, the inhibition of miR-199a-3p functions aggravated the myeloid proliferation defect in the Ercc1-deficient model, whereas its enforced expression enhanced proliferation of progenitors. Importantly, miR-199a-3p caused AML in a pre-leukemic mouse model, supporting its role as an onco-microRNA. Target genes include HuR for miR-139-3p and Prdx6, Runx1, and Suz12 for miR-199a-3p. The latter genes have previously been implicated as tumor suppressors in de novo and secondary AML. These findings show that, in addition to TRP53-controlled mechanisms, miR-139-3p and miR-199a-3p are involved in the defective hematopoietic function of ICL-repair deficient myeloid progenitors.
authors.affiliation: Department of Hematology, Erasmus University Medical Center Cancer Institute, Rotterdam, The Netherlands;
authors.forename: Mir Farshid
authors.initials: MF
authors.lastname: Alemdehy
authors.affiliation: Department of Hematology, Erasmus University Medical Center Cancer Institute, Rotterdam, The Netherlands;
authors.forename: Jurgen R
authors.initials: JR
authors.lastname: Haanstra
authors.affiliation: Department of Hematology, Erasmus University Medical Center Cancer Institute, Rotterdam, The Netherlands;
authors.forename: Hans W J
authors.initials: HW
authors.lastname: de Looper
authors.affiliation: Department of Hematology, Erasmus University Medical Center Cancer Institute, Rotterdam, The Netherlands;
authors.forename: Paulina M H
authors.initials: PM
authors.lastname: van Strien
authors.affiliation: Department of Hematology, Erasmus University Medical Center Cancer Institute, Rotterdam, The Netherlands;
authors.forename: Judith
authors.initials: J
authors.lastname: Verhagen-Oldenampsen
authors.affiliation: Department of Hematology, Erasmus University Medical Center Cancer Institute, Rotterdam, The Netherlands;
authors.forename: Yvette
authors.initials: Y
authors.lastname: Caljouw
authors.affiliation: Department of Hematology, Erasmus University Medical Center Cancer Institute, Rotterdam, The Netherlands;
authors.forename: Mathijs A
authors.initials: MA
authors.lastname: Sanders
authors.affiliation: Department of Hematology, Erasmus University Medical Center Cancer Institute, Rotterdam, The Netherlands;
authors.forename: Remco
authors.initials: R
authors.lastname: Hoogenboezem
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands;
authors.forename: Arnoud H
authors.initials: AH
authors.lastname: de Ru
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands;
authors.forename: George M C
authors.initials: GM
authors.lastname: Janssen
authors.affiliation: Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands; and.
authors.forename: Stephanie E
authors.initials: SE
authors.lastname: Smetsers
authors.affiliation: Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands; and Dutch Childhood Oncology Group, The Hague, The Netherlands.
authors.forename: Marc B
authors.initials: MB
authors.lastname: Bierings
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands;
authors.forename: Peter A
authors.initials: PA
authors.lastname: van Veelen
authors.affiliation: Department of Hematology, Erasmus University Medical Center Cancer Institute, Rotterdam, The Netherlands;
authors.forename: Marieke
authors.initials: M
authors.lastname: von Lindern
authors.affiliation: Department of Hematology, Erasmus University Medical Center Cancer Institute, Rotterdam, The Netherlands;
authors.forename: Ivo P
authors.initials: IP
authors.lastname: Touw
authors.affiliation: Department of Hematology, Erasmus University Medical Center Cancer Institute, Rotterdam, The Netherlands;
authors.forename: Stefan J
authors.initials: SJ
authors.lastname: Erkeland
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004260:DNA Repair / Q000235:genetics; D004268:DNA-Binding Proteins / Q000172:deficiency; D004195:Disease Models, Animal; D004720:Endonucleases / Q000172:deficiency; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology*; D007938:Leukemia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; C546202:MIRN139 microRNA, mouse; D035683:MicroRNAs; C534780:Mirn199 microRNA, mouse; D016159:Tumor Suppressor Protein p53; D004720:Endonucleases; C499360:Ercc1 protein, mouse