title: 5'UTR point substitutions and N-terminal truncating mutations of ANKRD26 in acute myeloid leukemia.
abstract: Thrombocytopenia 2 (THC2) is an inherited disorder caused by monoallelic single nucleotide substitutions in the 5'UTR of the ANKRD26 gene. Patients have thrombocytopenia and increased risk of myeloid malignancies, in particular, acute myeloid leukemia (AML). Given the association of variants in the ANKRD26 5'UTR with myeloid neoplasms, we investigated whether, and to what extent, mutations in this region contribute to apparently sporadic AML. To this end, we studied 250 consecutive, non-familial, adult AML patients and screened the first exon of ANKRD26 including the 5'UTR. We found variants in four patients. One patient had the c.-125T>G substitution in the 5'UTR, while three patients carried two different variants in the 5' end of the ANKRD26 coding region (c.3G>A or c.105C>G). Review of medical history showed that the patient carrying the c.-125T>G was actually affected by typical but unrecognized THC2, highlighting that some apparently sporadic AML cases represent the evolution of a well-characterized familial predisposition disorder. As regards the c.3G>A and the c.105C>G, we found that both variants result in the synthesis of N-terminal truncated ANKRD26 isoforms, which are stable and functional in cells, in particular, have a strong ability to activate the MAPK/ERK signaling pathway. Moreover, investigation of one patient with the c.3G>A showed that mutation was associated with strong ANKRD26 overexpression in vivo, which is the proposed mechanism for predisposition to AML in THC2 patients. These data provide evidence that N-terminal ANKRD26 truncating mutations play a potential pathogenetic role in AML. Recognition of AML patients with germline ANKRD26 pathogenetic variants is mandatory for selection of donors for bone marrow transplantation.
authors.affiliation: Medical Genetics Unit, Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Marconi
authors.affiliation: Department of Biology and Biotechnology, Laboratories of Biochemistry, University of Pavia, Pavia, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Canobbio
authors.affiliation: Department of Internal Medicine, IRCCS Policlinico San Matteo Foundation and University of Pavia, Pavia, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Bozzi
authors.affiliation: Medical Genetics Unit, Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.
authors.forename: Tommaso
authors.initials: T
authors.lastname: Pippucci
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology "L. and A. Seràgnoli", University of Bologna, Bologna, Italy.
authors.forename: Giorgia
authors.initials: G
authors.lastname: Simonetti
authors.affiliation: Department of Internal Medicine, IRCCS Policlinico San Matteo Foundation and University of Pavia, Pavia, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Melazzini
authors.affiliation: Medical Genetics Unit, Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Angori
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology "L. and A. Seràgnoli", University of Bologna, Bologna, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Martinelli
authors.affiliation: Department of Clinical and Biological Sciences, San Luigi Hospital, University of Turin, Orbassano, Turin, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Saglio
authors.affiliation: Department of Biology and Biotechnology, Laboratories of Biochemistry, University of Pavia, Pavia, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Torti
authors.affiliation: Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Ira
authors.initials: I
authors.lastname: Pastan
authors.affiliation: Medical Genetics Unit, Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Seri
authors.affiliation: Department of Internal Medicine, IRCCS Policlinico San Matteo Foundation and University of Pavia, Pavia, Italy. alessandro.pecci@unipv.it.
authors.forename: Alessandro
authors.identifier: 0000-0001-9202-7013
authors.initials: A
authors.lastname: Pecci
mesh_terms: D020121:5' Untranslated Regions / Q000235:genetics; D002471:Cell Transformation, Neoplastic; D019457:Chromosome Breakage; D025063:Chromosome Disorders / Q000150:complications / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006367:HeLa Cells; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D015470:Leukemia, Myeloid, Acute / Q000209:etiology / Q000235:genetics*; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*; D012333:RNA, Messenger / Q000097:blood; D013921:Thrombocytopenia / Q000150:complications / Q000151:congenital / Q000235:genetics; D014162:Transfection
chemical_list: D020121:5' Untranslated Regions; C583630:ANKRD26 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D012333:RNA, Messenger
keywords: ANKRD26 gene; Acute myeloid leukemia; Inherited predisposition to leukemia; Inherited thrombocytopenia