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Haploinsufficiency of the Hmga1 Gene Causes Cardiac Hypertrophy and Myelo-Lymphoproliferative Disorders in Mice

¹ Istituto di Endocrinologia ed Oncologia Sperimentale del Consiglio Nazionale delle Ricerche c/o Dipartimento di Biologia e Patologia Cellulare e Molecolare and ² Division of Cardiology, Università di Napoli "Federico II"; ³ Servizio di Immunoematologia e Medicina Trasfusionale, Ospedale A. Cardarelli; ⁴ Istituto dei Tumori di Napoli; ⁵ Naples Oncogenomic Center, CEINGE Biotecnologie Avanzate and European School of Molecular Medicine (Naples Site), Naples, Italy; ⁶ Division of Cardiology, Università di Catanzaro, Catanzaro, Italy; ⁷ Division of Human Cancer Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio; ⁸ Kimmel Cancer Center, Jefferson Medical College; ⁹ Experimental Histopathology, Fox Chase Cancer Center, Philadelphia, Pennsylvania

Requests for reprints: Alfredo Fusco, Dipartimento di Biologia e Patologia Cellulare e Molecolare, Università di Napoli Federico II, via S. Pansini 5, 80131 Naples, Italy. Phone: 39-81-746-3056; Fax: 39-81-746-3037; E-mail: afusco{at}napoli.com.

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. (Cancer Res 2006; 66(5): 2536-43)

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