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Blood, 1 December 2000, Vol. 96, No. 12, pp. 3887-3893
NEOPLASIA
A carboxy-terminal domain of ELL is required and sufficient for
immortalization of myeloid progenitors by MLL-ELL
Jorge F. DiMartino,
Trissa Miller,
Paul M. Ayton,
Theresa Landewe,
Jay L. Hess,
Michael L. Cleary, and
Ali Shilatifard
From the Department of Pathology and the Division of
Pediatric Hematology/Oncology, Stanford University School of Medicine,
Stanford, CA; the Department of Biochemistry, St Louis
University School of Medicine, St Louis, MO; and the
Department of Pathology and Laboratory Medicine, University of
Pennsylvania School of Medicine, Philadelphia, PA.
The t(11;19)(q23;p13.1) chromosomal translocation in acute myeloid
leukemias fuses the gene encoding transcriptional elongation factor ELL
to the MLL gene with consequent expression of an MLL-ELL chimeric protein. To identify potential mechanisms of leukemogenesis by
MLL-ELL, its transcriptional and oncogenic properties were investigated. Fusion with MLL preserves the transcriptional elongation activity of ELL but relocalizes it from a diffuse nuclear distribution to the nuclear bodies characteristic of MLL. Using a serial replating assay, it was demonstrated that the MLL-ELL chimeric protein is capable
of immortalizing clonogenic myeloid progenitors in vitro after its
retroviral transduction into primary murine hematopoietic cells.
However, a structure-function analysis indicates that the elongation
domain is not essential for myeloid transformation because mutants
lacking elongation activity retain a potent ability to immortalize
myeloid progenitors. Rather, the highly conserved carboxyl terminal R4
domain is both a necessary and a sufficient contribution from ELL for
the immortalizing activity associated with MLL-ELL. The R4 domain
demonstrates potent transcriptional activation properties and is
required for transactivation of a HoxA7 promoter by MLL-ELL
in a transient transcriptional assay. These data indicate that
neoplastic transformation by the MLL-ELL fusion protein is likely to
result from aberrant transcriptional activation of MLL
target genes. Thus, in spite of the extensive diversity of MLL fusion
partners, these data, in conjunction with previous studies of MLL-ENL,
suggest that conversion of MLL to a constitutive transcriptional
activator may be a general model for its oncogenic conversion in
myeloid leukemias.
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