Epigenetic Regulation of normal hematopoiesis and its dysregulation in myeloid neoplasia

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

  • Robert Slany

    University of Erlangen-Nuremberg
    Erwin-Rommel-Str. 3
    D-91058 Erlangen, Germany
    Phone +49-9131-85-28527
    Fax +49-9131-85-28526




    Emanuel Mäthner
    Renate Zimmermann