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Prepublished online as a Blood First Edition Paper on August 22, 2002; DOI 10.1182/blood-2002-06-1785.
Submitted June 24, 2002
Accepted August 13, 2002
Common mechanism for oncogenic activation of MLL by forkhead family proteins
Chi Wai So and Michael L Cleary*
Departments of Pathology and Pediatrics, Stanford University Medical Center, Stanford, CA, USA
* Corresponding author; email: michael.cleary{at}stanford.edu.
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 two 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 two 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 establish a bifunctional transcriptional contribution of forkhead family proteins to the oncogenic conversion of MLL and further support a specific role for fusion partners in determining pathologic features of the leukemia phenotype.
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