Haploinsufficiency of the Hmga1 gene causes cardiac hypertrophy and myelo-lymphoproliferative disorders in mice

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.