title: Inactivation of ribosomal protein L22 promotes transformation by induction of the stemness factor, Lin28B.
abstract: Ribosomal protein (RP) mutations in diseases such as 5q- syndrome both disrupt hematopoiesis and increase the risk of developing hematologic malignancy. However, the mechanism by which RP mutations increase cancer risk has remained an important unanswered question. We show here that monoallelic, germline inactivation of the ribosomal protein L22 (Rpl22) predisposes T-lineage progenitors to transformation. Indeed, RPL22 was found to be inactivated in ∼ 10% of human T-acute lymphoblastic leukemias. Moreover, monoallelic loss of Rpl22 accelerates development of thymic lymphoma in both a mouse model of T-cell malignancy and in acute transformation assays in vitro. We show that Rpl22 inactivation enhances transformation potential through induction of the stemness factor, Lin28B. Our finding that Rpl22 inactivation promotes transformation by inducing expression of Lin28B provides the first insight into the mechanistic basis by which mutations in Rpl22, and perhaps some other RP genes, increases cancer risk.
authors.affiliation: Blood Cell Development and Cancer Keystone, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
authors.forename: Shuyun
authors.initials: S
authors.lastname: Rao
authors.forename: Sang-Yun
authors.initials: SY
authors.lastname: Lee
authors.forename: Alejandro
authors.initials: A
authors.lastname: Gutierrez
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Perrigoue
authors.forename: Roshan J
authors.initials: RJ
authors.lastname: Thapa
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Tu
authors.forename: John R
authors.initials: JR
authors.lastname: Jeffers
authors.forename: Michele
authors.initials: M
authors.lastname: Rhodes
authors.forename: Stephen
authors.initials: S
authors.lastname: Anderson
authors.forename: Tamas
authors.initials: T
authors.lastname: Oravecz
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Hunger
authors.forename: Roman A
authors.initials: RA
authors.lastname: Timakhov
authors.forename: Rugang
authors.initials: R
authors.lastname: Zhang
authors.forename: Siddharth
authors.initials: S
authors.lastname: Balachandran
authors.forename: Gerard P
authors.initials: GP
authors.lastname: Zambetti
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Testa
authors.forename: A Thomas
authors.initials: AT
authors.lastname: Look
authors.forename: David L
authors.initials: DL
authors.lastname: Wiest
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D024202:Electrophoretic Mobility Shift Assay; D005434:Flow Cytometry; D020868:Gene Silencing; D019337:Hematologic Neoplasms / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D051379:Mice; D008822:Mice, Transgenic; D020411:Oligonucleotide Array Sequence Analysis; D016601:RNA-Binding Proteins / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D012269:Ribosomal Proteins / Q000235:genetics*; D013601:T-Lymphocytes / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; C570876:Lin28b protein, mouse; D016601:RNA-Binding Proteins; C522051:RPL22 protein, mouse; D012269:Ribosomal Proteins