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Mol. Cell. Biol., 01 1998, 122-129, Vol 18, No. 1
RK Slany, C Lavau and ML Cleary
The HRX gene (also called MLL, ALL-1, and Htrx) at chromosome band 11q23 is
associated with specific subsets of acute leukemias through translocations
that result in its fusion with a variety of heterologous partners. Two of
these partners, ENL and AF9, code for proteins that are highly similar to
each other and as fusions with HRX induce myeloid leukemias in mice as
demonstrated by retroviral gene transfer and knock- in experiments,
respectively. In the present study, a structure- function analysis was
performed to determine the molecular requirements for in vitro
immortalization of murine myeloid cells by HRX-ENL. Deletions of either the
AT hook motifs or the methyltransferase homology domain of HRX
substantially impaired the transforming effects of HRX-ENL. The
methyltransferase homology domain was shown to bind non- sequence
specifically to DNA in vitro, providing evidence that the full transforming
activity of HRX-ENL requires multiple DNA binding structures in HRX. The
carboxy-terminal 84 amino acids of ENL, which encode two predicted helical
structures highly conserved in AF9, were necessary and sufficient for
transformation when they were fused to HRX. Similarly, mutations that
deleted one or both of these conserved helices completely abrogated the
transcriptional activation properties of ENL. This finding correlates, for
the first time, a biological function of an HRX fusion partner with the
transforming activity of the chimeric proteins. Our studies support a model
in which HRX-ENL induces myeloid transformation by deregulating subordinate
genes through a gain of function contributed by the transcriptional
effector properties of ENL.
Copyright © 1998, American Society for Microbiology
The oncogenic capacity of HRX-ENL requires the transcriptional transactivation activity of ENL and the DNA binding motifs of HRX
Department of Pathology, Stanford University Medical Center, California 94305, USA.
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