Partial Loss of Rpl11 in Adult Mice Recapitulates Diamond-Blackfan Anemia and Promotes Lymphomagenesis.
Diamond-Blackfan anemia (DBA) is characterized by anemia and cancer susceptibility and is caused by mutations in ribosomal genes, including RPL11. Here, we report that Rpl11-heterozygous mouse embryos are not viable and that Rpl11 homozygous deletion in adult mice results in death within a few weeks, accompanied by bone marrow aplasia and intestinal atrophy. Importantly, Rpl11 heterozygous deletion in adult mice results in anemia associated with decreased erythroid progenitors and defective erythroid maturation. These defects are also present in mice transplanted with inducible heterozygous Rpl11 bone marrow and, therefore, are intrinsic to the hematopoietic system. Additionally, heterozygous Rpl11 mice present increased susceptibility to radiation-induced lymphomagenesis. In this regard, total or partial deletion of Rpl11 compromises p53 activation upon ribosomal stress or DNA damage in fibroblasts. Moreover, fibroblasts and hematopoietic tissues from heterozygous Rpl11 mice present higher basal cMYC levels. We conclude that Rpl11-deficient mice recapitulate DBA disorder, including cancer predisposition.
Tumor Suppression Group, Molecular Oncology Programme, Spanish National Cancer Research Centre (CNIO), Madrid E28029, Spain.
Lucia
L
Morgado-Palacin
Tumor Suppression Group, Molecular Oncology Programme, Spanish National Cancer Research Centre (CNIO), Madrid E28029, Spain.
Gianluca
G
Varetti
Tumor Suppression Group, Molecular Oncology Programme, Spanish National Cancer Research Centre (CNIO), Madrid E28029, Spain.
Susana
S
Llanos
Bioniformatics Unit, Structural Biology and Biocomputing Programme, Spanish National Cancer Research Centre (CNIO), Madrid E28029, Spain.
Gonzalo
G
Gómez-López
Flow Cytometry Unit, Biotechnology Programme, Spanish National Cancer Research Centre (CNIO), Madrid E28029, Spain.
Dolores
D
Martinez
Tumor Suppression Group, Molecular Oncology Programme, Spanish National Cancer Research Centre (CNIO), Madrid E28029, Spain. Electronic address: mserrano@cnio.es.
Manuel
M
Serrano
D029503:Anemia, Diamond-Blackfan / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D041905:Erythroid Cells / Q000378:metabolism; D008223:Lymphoma / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D012269:Ribosomal Proteins / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
D012269:Ribosomal Proteins; D016159:Tumor Suppressor Protein p53