Epigenetic consequences of MLL fusion protein expression
Final Report Abstract
MLL fusion proteins are the result of chromosomal aberrations occurring in an aggressive subtype of acute leukemia. These chimeric proteins interact with and change the function of various proteins involved in normal transcription and thus perturb the proper expression of a set of target genes ultimately leading to cellular transformation. The purpose of this research project was to elucidate how these interactions modify chromatin states and how they alter the transcriptional activity of RNA polymerase in addition to identifying all direct target genes on a molecular level. Applying biochemical and genome-wide molecular biology techniques like time-resolved nascentRNA and ChIP-sequencing in a defined knock-in model of a paradigmatic MLL-ENL fusion revealed that MLL fusions activate transcription by two alternative pathways depending on the respective environment. Either they cause excessive chromatin modification by recruiting the DOT1L histone methyltransferase or they associate with the positive transcription elongation factor B to stimulate progression of RNA Polymerase II leading to extraordinary high transcription rates. In both instances activity is dependent on a constitutive recruitment of PAF1 and associated factors that alleviate repressive chromatin conformations imposed by the polycomb repressive complex. In this way MLL fusions not only remove transcriptional impediments that normally restrict transcriptional output but they also abnormally increase transcription speed leading to a relative overexpression of their direct target genes. The clarification of the molecular nature of this process identified new molecules that can serve as therapeutic targets and the dichotomic nature of MLL-ENL function explains why trials inhibiting only one of the two activities have not been successful yet. Overall this study delivers a rational base on which new strategies for treating this severe disease can be explored.
Publications
- (2012) DNA Damage Response and Inflammatory Signaling Limit the MLL-ENL induced Leukemogenesis in vivo. Cancer Cell,21(4):517-531
Takacova S., Slany R., Bartkova J., Stranecky V., Dolezel P., Luzna P., Bartek J., Divoky V.
(See online at https://doi.org/10.1016/j.ccr.2012.01.021) - (2013) MLL-ENL inhibits Polycomb repressive complex 1 to achieve efficient transformation of hematopoietic cells. Cell Reports
Maethner E., Garcia-Cuellar M.P., Breitinger C., Takacova S., Divoky V., Hess J.L., and Slany R.K.
(See online at https://doi.org/10.1016/j.celrep.2013.03.038) - (2014) DOTting the Path to Doom: How Acceleration of Histone Methylation Leads to Leukemia. Comment, Cancer Cell. 8;26(6):781-782
Bach C., and Slany R.K.
(See online at https://doi.org/10.1016/j.ccell.2014.11.004) - (2016) Leukemogenic MLL- ENL fusions induce alternative chromatin states to drive a functionally dichotomous group of target genes. CellReports, pii: S2211-1247(16)30259-5
Garcia-Cuellar MP, Büttner C, Bartenhagen C, Dugas C, Slany RK
(See online at https://doi.org/10.1016/j.celrep.2016.03.018) - (2016) Protein kinase Msk1 physically and functionally interacts with the KMT2A/MLL1 methyltransferase complex and contributes to the regulation of multiple target genes. Epigenetics Chromatin. 9:52
Wiersma M, Bussiere M, Halsall JA, Turan N, Slany R, Turner BM, and Nightingale KP
(See online at https://doi.org/10.1186/s13072-016-0103-3) - (2016) The molecular mechanics of mixed lineage leukemia. Oncogene, Review, 35(40):5215-5223
Slany R.K.
(See online at https://doi.org/10.1038/onc.2016.30) - (2017) AML1-ETO requires enhanced C/D box snoRNA/RNP formation to induce self-renewal and leukemia. NatureCellBiology, Jun 26
Zhou F, Liu Y, Rohde C, Pauli C, Gerloff D, Köhn M, Misiak D, Bäumer N, Cui C, Göllner S, Oellerich T, Serve H, Garcia-Cuellar MP, Slany R, Maciejewski JP, Przychodzen B, Seliger B, Klein HU, Bartenhagen C, Berdel WE, Dugas M, Taketo MM, Farouq D, Schwartz S, Regev A, Hébert J, Sauvageau G, Pabst C, Hüttelmaier S, and Müller-Tidow C
(See online at https://doi.org/10.1038/ncb3563) - (2017) The interaction of ENL with PAF1 mitigates polycomb silencing and facilitates murine leukemogenesis. Blood
Hetzner K, Garcia-Cuellar MP, Büttner C, Slany RK
(See online at https://doi.org/10.1182/blood-2017-11-815035)
