Epigenetic consequences of MLL fusion protein expression
MLL fusion proteins are potent inducers of acute leukemia. These proteins
are created by chromosomal translocations that juxtapose the amino-terminus
of the histone methyltransferase MLL with a variety of different partner
proteins. As a consequence genes normally controlled by wild-type MLL, like
the clustered HOX homeobox genes, are brought under the influence of
partner-recruited activities.
The fusion partners of the ENL- and AF4-family
are members of a multiprotein complex that modifies chromatin and promotes
transcriptional elongation through DOT1L and pTEFb. DOT1L is a histone H3
lysine79 specific methyltransferase and pTEFb phosphorylates the
carboxy-terminal repeat region of RNA Polymerase II. Paradoxically, this
complex also includes polycomb-type repressors.
This project tries to
understand MLL fusion biology in myeloid development by pursuing three
specific aims:
a) Studying the interplay of MLL-ENL mediated chromatin modifications with
normal epigenetic HOX regulation
b) Deciphering the role of H3K79 methylation in transcriptional control and leukemogenesis
c) Mapping the epigenetic landscape of the HOXA locus in normal and MLL-ENL transformed myeloid cells
Slany R.K. (2010). When speed matters: Leukemogenic transformation by MLL fusion proteins. Cell Cycle, 9(13).
PMID:20543578
Müller D., Garcia-Cuellar M.P., Bach C., Buhl S., Mäthner E., and Slany R.K. (2009). Misguided Transcriptional Elongation Causes Mixed Lineage Leukemia, PLOS Biology, 7(11):e1000249.
PMID:19956800
Müller D., Bach C., Zeisig D., Garcia-Cuellar M.P., Monroe S., Sreekumar A., Zhou R., Nesvizhskii A., Chinnaiyan A., Hess J.L., and Slany R.K. (2007). A Role for the MLL Fusion Partner ENL in Transcriptional Elongation and Chromatin Modification, Blood, 110: 4445-4454.
PMID:17855633
Monroe S.C., Joa S.Y., Sandersa D.S., Basrura V., Elenitoba-Johnsona K.S., Slany R.K., and Hess J.L. (2011). MLL-AF9 alters the dynamic association of transcriptional regulators with leukemogenic target genes, Exp.Hematol,
39:77-86.
PMID:20854876