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Prepublished online as a Blood First Edition Paper on August 22, 2002; DOI 10.1182/blood-2002-06-1785.
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Blood, 15 January 2003, Vol. 101, No. 2, pp. 633-639
NEOPLASIA
Common mechanism for oncogenic activation of MLL by forkhead
family proteins
Chi Wai So and
Michael L. Cleary
From the Department of Pathology, Stanford University
School of Medicine, Stanford, CA.
The mixed lineage leukemia (MLL) gene undergoes
fusions with a diverse set of genes as a consequence of chromosomal
translocations in acute leukemias. Two of these partner genes code for
members of the forkhead subfamily of transcription factors designated FKHRL1 and AFX. We demonstrate here that MLL-FKHRL1 enhances the self-renewal of murine myeloid progenitors in vitro and induces acute
myeloid leukemias in syngeneic mice. The long latency (mean = 157
days), reduced penetrance, and hematologic features of the leukemias
were very similar to those observed for the forkhead fusion protein
MLL-AFX and contrasted with the more aggressive features of leukemias
induced by MLL-AF10. Transformation mediated by MLL-forkhead fusion
proteins required 2 conserved transcriptional effector domains (CR2 and
CR3), each of which alone was not sufficient to activate MLL. A
synthetic fusion of MLL with FKHR, a third mammalian forkhead family
member that contains both effector domains, was also capable of
transforming hematopoietic progenitors in vitro. A comparable
requirement for 2 distinct transcriptional effector domains was also
displayed by VP16, which required its proximal minimal transactivation
domain (MTD/H1) and distal H2 domain to activate the oncogenic
potential of MLL. The functional importance of CR2 was further
demonstrated by its ability to substitute for H2 of VP16 in
domain-swapping experiments to confer oncogenic activity on MLL. Our
results, based on bona fide transcription factors as partners for MLL,
unequivocally establish a transcriptional effector mechanism to
activate its oncogenic potential and further support a role for fusion
partners in determining pathologic features of the leukemia phenotype.
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