title: Haploinsufficiency of the Hmga1 gene causes cardiac hypertrophy and myelo-lymphoproliferative disorders in mice.
abstract: The HMGA1 protein is a major factor in chromatin architecture and gene control. It plays a critical role in neoplastic transformation. In fact, blockage of HMGA1 synthesis prevents rat thyroid cell transformation by murine transforming retroviruses, and an adenovirus carrying the HMGA1 gene in the antisense orientation induces apoptotic cell death in anaplastic human thyroid carcinoma cell lines, but not in normal thyroid cells. Moreover, both in vitro and in vivo studies have established the oncogenic role of the HMGA1 gene. In this study, to define HMGA1 function in vivo, we examined the consequences of disrupting the Hmga1 gene in mice. Both heterozygous and homozygous mice for the Hmga1-null allele show cardiac hypertrophy due to the direct role of HMGA1 on cardiomyocytic cell growth regulation. These mice also developed hematologic malignancies, including B cell lymphoma and myeloid granuloerythroblastic leukemia. The B cell expansion and the increased expression of the RAG1/2 endonuclease, observed in HMGA1-knockout spleen tissues, might be responsible for the high rate of abnormal IgH rearrangements observed in these neoplasias. Therefore, the data reported here indicate the critical role of HMGA1 in heart development and growth, and reveal an unsuspected antioncogenic potential for this gene in hematologic malignancies.
authors.affiliation: Istituto di Endocrinologia ed Oncologia Sperimentale del Consiglio Nazionale delle Ricerche c/o Dipartimento di Biologia e Patologia Cellulare e Molecolare, Università di Napoli Federico II, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Fedele
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Fidanza
authors.forename: Sabrina
authors.initials: S
authors.lastname: Battista
authors.forename: Francesca
authors.initials: F
authors.lastname: Pentimalli
authors.forename: Andres J P
authors.initials: AJ
authors.lastname: Klein-Szanto
authors.forename: Rosa
authors.initials: R
authors.lastname: Visone
authors.forename: Ivana
authors.initials: I
authors.lastname: De Martino
authors.forename: Antonio
authors.initials: A
authors.lastname: Curcio
authors.forename: Carmine
authors.initials: C
authors.lastname: Morisco
authors.forename: Luigi
authors.initials: L
authors.lastname: Del Vecchio
authors.forename: Gustavo
authors.initials: G
authors.lastname: Baldassarre
authors.forename: Claudio
authors.initials: C
authors.lastname: Arra
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Viglietto
authors.forename: Ciro
authors.initials: C
authors.lastname: Indolfi
authors.forename: Carlo M
authors.initials: CM
authors.lastname: Croce
authors.forename: Alfredo
authors.initials: A
authors.lastname: Fusco
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000473:pathology; D006332:Cardiomegaly / Q000235:genetics* / Q000276:immunology; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D025741:HMGA1a Protein / Q000172:deficiency / Q000235:genetics* / Q000276:immunology; D006238:Haploidy; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D007378:Interleukins / Q000096:biosynthesis / Q000235:genetics; D016393:Lymphoma, B-Cell / Q000235:genetics / Q000276:immunology; D008232:Lymphoproliferative Disorders / Q000235:genetics* / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051381:Rats; D017208:Rats, Wistar
chemical_list: D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D007378:Interleukins; C499308:Rag2 protein, mouse; D025741:HMGA1a Protein; C064658:RAG-1 protein