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Blood, 15 May 2002, Vol. 99, No. 10, pp. 3780-3785
NEOPLASIA
The AF10 leucine zipper is required for leukemic transformation
of myeloid progenitors by MLL-AF10
Jorge F. DiMartino,
Paul M. Ayton,
Everett H. Chen,
Clarissa C. Naftzger,
Bryan D. Young, and
Michael L. Cleary
From the Departments of Pathology and Pediatrics,
Stanford University School of Medicine, CA; Planet Biotechnology,
Hayward, CA; and ICRF Department of Medical Oncology, Medical College
of St Bartholomew's Hospital, London, United Kingdom.
The t(10;11)(p12;q23) chromosomal translocation in human
acute myeloid leukemia results in the fusion of the
MLL and AF10 genes. The latter codes
for a novel leucine zipper protein, one of many MLL fusion partners of
unknown function. In this report, we demonstrate that
retroviral-mediated transduction of an MLL-AF10 complementary DNA into primary murine myeloid progenitors enhanced their clonogenic potential in serial replating assays and led to their
efficient immortalization at a primitive stage of myeloid differentiation. Furthermore, MLL-AF10-transduced cells rapidly induced acute myeloid leukemia in syngeneic or severe combined immunodeficiency recipient mice. Structure/function analysis showed that a highly conserved 82-amino acid portion of AF10, comprising 2 adjacent  -helical domains, was sufficient for immortalizing activity
when fused to MLL. Neither helical domain alone mediated immortalization, and deletion of the 29-amino acid leucine zipper within this region completely abrogated transforming activity. Similarly, the minimal oncogenic domain of AF10 exhibited
transcriptional activation properties when fused to the MLL or GAL4
DNA-binding domains, while neither helical domain alone did. However,
transcriptional activation per se was not sufficient because a second
activation domain of AF10 was neither required nor competent for
transformation. The requirement for -helical transcriptional
effector domains is similar to the oncogenic contributions of unrelated
MLL partners ENL and ELL, suggesting a general mechanism of myeloid
leukemogenesis by a subset of MLL fusion proteins, possibly through
specific recruitment of the transcriptional machinery.
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