1: Oncogene. 2000 Feb 3;19(5):608-16. 

HoxA9-mediated immortalization of myeloid progenitors requires functional
interactions with TALE cofactors Pbx and Meis.

Schnabel CA, Jacobs Y, Cleary ML.

Department of Pathology, Stanford University School of Medicine, California
94305, USA.

Specific Hox genes are implicated in leukemic transformation, and their
selective genetic collaboration with TALE homeobox genes, Pbx and Meis,
accentuates their oncogenic potential. The molecular mechanisms underlying these
coordinate functions, however, have not been characterized. In this study, we
demonstrate that HoxA9 requires its Pbx interaction motif as well as its amino
terminus to enhance the clonogenic potential of myeloid progenitors in vitro. We
further show that HoxA9 forms functional trimeric DNA binding complexes with Pbx
and Meis-like proteins on a modified enhancer. DNA binding complexes containing
HoxA9 and TALE homeoproteins display cooperative transcriptional activity and
are present in leukemic cells. Trimeric complex formation on its own, however,
is not sufficient for HoxA9-mediated immortalization. Rather, structure-function
analyses demonstrate that domains of HoxA9 which are necessary for cellular
transformation are coincident with those required for trimer-mediated
transcriptional activation. Furthermore, the amino terminus of HoxA9 provides
essential transcriptional effector properties and its requirement for myeloid
transformation can be functionally replaced by the VP16 activation domain. These
data suggest that biochemical interactions between HoxA9 and TALE homeoproteins
mediate cellular transformation in hematopoietic cells, and that their
transcriptional activity in higher order DNA binding complexes provides a
molecular basis for their collaborative roles in leukemogenesis.

PMID: 10698505 [PubMed - indexed for MEDLINE]


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