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Molecular and Cellular Biology, August 2001, p. 5678-5687, Vol. 21, No. 16
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.16.5678-5687.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

The Elongation Domain of ELL Is Dispensable but Its ELL-Associated Factor 1 Interaction Domain Is Essential for MLL-ELL-Induced Leukemogenesis

Roger T. Luo,1 Catherine Lavau,2,* Changchun Du,2 Federico Simone,1 Paul E. Polak,1 Shin Kawamata,2 and Michael J. Thirman1,*

Section of Hematology/Oncology, University of Chicago, Chicago, Illinois 60637,1 and Systemix, Palo Alto, California 943042

Received 29 December 2000/Returned for modification 28 February 2001/Accepted 8 May 2001

The MLL-ELL chimeric gene is the product of the (11;19)(q23p13.1) translocation associated with de novo and therapy-related acute myeloid leukemias (AML). ELL is an RNA polymerase II elongation factor that interacts with the recently identified EAF1 (ELL associated factor 1) protein. EAF1 contains a limited region of homology with the transcriptional activation domains of three other genes fused to MLL in leukemias, AF4, LAF4, and AF5q31. Using an in vitro transformation assay of retrovirally transduced myeloid progenitors, we conducted a structure-function analysis of MLL-ELL. Whereas the elongation domain of ELL was dispensable, the EAF1 interaction domain of ELL was critical to the immortalizing properties of MLL-ELL in vitro. To confirm these results in vivo, we transplanted mice with bone marrow transduced with MLL fused to the minimal EAF1 interaction domain of ELL. These mice all developed AML, with a longer latency than mice transplanted with the wild-type MLL-ELL fusion. Based on these results, we generated a heterologous MLL-EAF1 fusion gene and analyzed its transforming potential. Strikingly, we found that MLL-EAF1 immortalized myeloid progenitors in the same manner as that of MLL-ELL. Furthermore, transplantation of bone marrow transduced with MLL-EAF1 induced AML with a shorter latency than mice transplanted with the MLL-ELL fusion. Taken together, these results indicate that the leukemic activity of MLL-ELL requires the EAF1 interaction domain of ELL, suggesting that the recruitment by MLL of a transactivation domain similar to that in EAF1 or the AF4/LAF4/AF5q31 family may be a critical common feature of multiple 11q23 translocations. In addition, these studies support a critical role for MLL partner genes and their protein-protein interactions in 11q23 leukemogenesis.

* Corresponding author. Mailing address for Michael J. Thirman: 5841 South Maryland Ave., MC2115, Chicago, IL 60637. Phone: (773) 702-4133. Fax: (773) 702-8702. E-mail: mthirman{at}medicine.bsd.uchicago.edu. Present address for Catherine Lavau: CNRS UPR9051, IUH, Paris 75010, France. E-mail: catlav{at}chu-stlouis.fr.

Molecular and Cellular Biology, August 2001, p. 5678-5687, Vol. 21, No. 16
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.16.5678-5687.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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