title: The human NPM1 mutation A perturbs megakaryopoiesis in a conditional mouse model.
abstract: The NPM1 mutation is the most frequent genetic alteration thus far identified in acute myeloid leukemia (AML). Despite progress in the clinical and biological characterization of NPM1-mutated AML, the role of NPM1 mutation in leukemogenesis in vivo has not been fully elucidated. We report a novel mouse model that conditionally expresses the most common human NPM1 mutation (type A) in the hematopoietic compartment. In Npm1-TCTG/WT;Cre(+) mice, the NPM1 mutant localized in the cytoplasm (NPMc(+)) of bone marrow (BM) cells. The mutant mice developed no AML after 1.5-year follow-up. However, NPMc(+) expression determined a significant platelet count reduction and an expansion of the megakaryocytic compartment in the BM and spleen. Serum thrombopoietin levels overlapped in mutant vs control mice, and BM cells from Npm1-TCTG/WT;Cre(+) mice formed more megakaryocytic colonies in vitro. Moreover, we demonstrated the up-regulation of microRNAs (miRNAs; miR-10a, miR-10b, and miR-20a) inhibiting megakaryocytic differentiation along with increased expression of HOXB genes. Notably, these findings mimic those of human NPM1-mutated AML, which also exhibits a similar miRNA profile and expansion of the megakaryocytic compartment. Our mouse model provides evidence that the NPM1 mutant affects megakaryocytic development, further expanding our knowledge of the role of NPM1 mutant in leukemogenesis.
authors: Institute of Hematology, University of Perugia, Ospedale S. Mariadella Misericordia, Perugia, Italy. sportolp@gmail.com
authors: Paolo
authors: P
authors: Sportoletti
authors: Emanuela
authors: E
authors: Varasano
authors: Roberta
authors: R
authors: Rossi
authors: Oxana
authors: O
authors: Bereshchenko
authors: Debora
authors: D
authors: Cecchini
authors: Ilaria
authors: I
authors: Gionfriddo
authors: Niccolò
authors: N
authors: Bolli
authors: Enrico
authors: E
authors: Tiacci
authors: Tamara
authors: T
authors: Intermesoli
authors: Pamela
authors: P
authors: Zanghì
authors: Arianna
authors: A
authors: Masciulli
authors: Maria Paola
authors: MP
authors: Martelli
authors: Franca
authors: F
authors: Falzetti
authors: Massimo F
authors: MF
authors: Martelli
authors: Brunangelo
authors: B
authors: Falini
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002454:Cell Differentiation; D049109:Cell Proliferation; D003114:Colony-Forming Units Assay; D004195:Disease Models, Animal; D005434:Flow Cytometry; D006801:Humans; D007124:Immunoenzyme Techniques; D019426:Integrases / Q000378:metabolism*; D015470:Leukemia, Myeloid, Acute / Q000209:etiology* / Q000473:pathology; D008533:Megakaryocytes / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D000090243:Nucleophosmin; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D034061:Thrombopoiesis / Q000235:genetics*
chemical_list: D035683:MicroRNAs; C000716967:NPM1 protein, human; C000715570:Npm1 protein, mouse; D009687:Nuclear Proteins; D012333:RNA, Messenger; D000090243:Nucleophosmin; C045073:Cre recombinase; D019426:Integrases