Transcriptional activation is a key function encoded by MLL fusion partners

Abstract

Chromosomal translocations that fuse the mixed lineage leukemia gene (MLL) to a variety of unrelated partner genes are frequent in pediatric leukemias. The novel combination of genetic material leads to the production of active oncoproteins that depend on the contributions of both constituents. In a search for a common function amongst the diverse group of MLL fusion partners we constructed artificial fusions joining MLL with generic transactivator and repressor domains (acidic blob, GAL4 transactivator domain, Herpes simplex VP16 activation domain, KRAB repressor domain). Of all constructs tested, only MLL-VP16 was able to transform primary bone marrow cells and to induce a block of early myeloid differentiation like an authentic MLL fusion. Interestingly, the transformation capability of the artificial MLL fusions was correlated with the transcriptional potential of the resulting chimeric protein but it was not related to the strength of the isolated transactivation domain that was joined to MLL. These results prove for the first time that a general biological function -transactivation -might be the common denominator of many MLL fusion partners.

Functional contribution of EEN to leukemogenic transformation by MLL-EEN fusion protein

“…Previous studies strongly suggest that the transcriptional effector functions of MLL fusion partners are essential for leukemogenesis (Ayton and Cleary, 2001;Zeisig et al, 2003). The ability of MLL-ENL, MLL-ELL, MLL-CBP, MLL-AFX and MLL-FKHRL1 to immortalize myeloid progenitors correlates well with their ability to transactivate reporter genes in transient transcriptional assays (Slany et al, 1998;Dimartino et al, 2000;Lavau et al, 2000;So and Cleary, 2002;.…”

Binding to Nonmethylated CpG DNA Is Essential for Target Recognition, Transactivation, and Myeloid Transformation by an MLL Oncoprotein

“…These genetic events lead to the production of dominant-acting oncogenic fusion proteins that invariably consist of the N-terminal 1,400 residues of MLL fused to variable portions of the partner protein. The results of structure-function studies of a subset of MLL fusion proteins suggest a common theme whereby transcriptional effector domains of the partner proteins make critical contributions to the oncogenicity of MLL fusion proteins (8,9,18,22,(32)(33)(34)43). The consistent inclusion of the N-terminal 1,400 residues in all described MLL fusion proteins suggests that it contributes critical common functions to leukemogenesis, although the mechanistic basis for such functions remains poorly defined.…”

The eleven-nineteen-leukemia protein ENL connects nuclear MLL fusion partners with chromatin

“…This is achieved either by dimerization of the MLL N-terminus (Martin et al, 2003;So and Cleary, 2004) or through a direct connection with a transactivator domain derived from the respective partner (Slany et al, 1998;So and Cleary, 2002). Interestingly, not all generic transactivators fused to MLL are capable of transformation (Zeisig et al, 2003b). The experimental evidence suggests that activation domains conferring oncogenic properties to MLL must simultaneously recruit chromatin modifying activities and the RNA polymerase II transcription machinery .…”