Rolf Marschalek

 

Department of Biochemistry, Chemistry & PharmacyMarschalek

Goethe-University of Frankfurt

Germany

Director Institute Pharm Biology

Director DCAL (Diagnostic Center of Acute Leukemia)

Telephone: +49 69-798-29647

Fax: +49 69-798-29662

E-mail: rolf.marschalek@em.uni-frankfurt.de

Principal areas of expertise: Molecular Hemato-Oncology 

  

 

MLL-mediated leukemias – molecular mechanisms of cancer

Infant acute leukaemias are classified as aggressive tumours that need high amounts of polychemotherapy for treatment, although the outcome is still poor. Genetically, the group of pediatric leukemia patients is characterized by distinct genetic rearrangements of the MLL gene located at 11q23. Several improvements in treatment have been achieved over the last decades (see recent AIEOP-, BFM-, USA-studies), but the general situation for this group of leukemia patients is still unsatisfying when treated solely by chemotherapy. In line with this argument, a recent study demonstrated the benefits of hematopoietic stem cell transplantation on the overall and disease free survival of pediatric leukemia patients that bear MLL rearrangements (Mann et al., 2010). However, alternative strategies are still necessary to further improve outcome. The use of novel therapeutics, however, is only possible if the pathological disease mechanisms are clearly understood and rational drug design comes into play. Therefore, it is of importance to evaluate the existing data and to draw correct conclusions.

Historically, MLL fusion proteins have been early on recognized as transcriptional deregulators of distinct HOX genes (Kawagoe et al., 1999; Imanmura et al., 2002; Ayton & Clary, 2003). Therefore, a “common denominator concept” has been proposed, claiming that all MLL fusion proteins work by a similar concept: they increase and maintain high level transcription of MEIS1 and HOXA gene family members. A physical association of MEN1, LEDGF and MYB protein at the N-terminal portion of the MLL fusion protein is of functional importance (Milne et al., 2005; Caslini et al., 2007; Yokoyama & Cleary, 2008; Jin et al., 2010). Deregulated HOXA gene expression inflicts proper haematopoietic development, and subsequently, initiates the development of pre- or leukemic cell clones.

Our focus lies on the diagnosis of MLL-rearranged leukemias. In addition, we investigate the functional properties of MLL fusion proteins. In particular, we are focussed on t(4;11) translocations that result in the expression of MLL-AF4 and AF4-MLL fusion proteins. Patients bearing a t(4;11) translocation are frequently diagnosed in the first after birth. The patients have very high white blood cell counts, are difficult to treat and display a dismal outcome.

We have recently shown that the sole expression of AF4-MLL result in proB and mixed-lineage leukemia in a murine model system (Bursen  et al., 2010). We have also unravelled the molecular function of the AF4-MLL fusion protein (Benedikt et al., 2011). This led us to a completely new field of research, namely the „control of transcriptional elongation“, which is severly disturbed in the presence of AF4-MLL. This fusion protein reprograms cells at the transcriptional and epigenetic level, allowing to regain stem cell features

Within this general line of research, specific projects are:

  1. Mouse models and xenograft models for MLL-fusion proteins
  2. Epigenetic research
  3. Transcriptional elongation control
  4. Molecular mechanisms of chromosomal rearrangements 

 

Key publications (selected from 157 publications):

Meyer C, Zur Stadt U, Escherich G, Hofmann J, Binato R, Barbosa Tda C, Emerenciano M, Pombo-de-Oliveira MS, Horstmann M, Marschalek R (2013) Refinement of IKZF1 recombination hotspots in pediatric BCP-ALL patients. Am J Blood Res 3: 165-173

Meyer C, et al. (2013) The MLL recombinome of acute leukemias in 2013. Leukemia, doi: 10.1038/leu.2013.135

Prelle C, Bursen A, Dingermann T, Marschalek R (2013) Secondary mutations in t(4;11) leukemia patients. Leukemia 27: 1425-1427

Scholz B, Marschalek R (2012) Epigenetics and blood disorders. Br J Haematol 158: 307-322

Pless B, Oehm C, Knauer S, Stauber RH, Dingermann T, Marschalek R (2011) The heterodimerization domains of MLL – FYRN and FYRC – are potential target structures in t(4;11) leukemia. Leukemia 25: 663-670

Marschalek R (2011) Mechanisms of leukemogenesis by MLL fusion proteins. Br J Haematol 152: 141-154

Benedikt A, Baltruschat S, Scholz B, Bursen A, Arrey TN, Meyer B, Varagnolo L, Müller A, Karas M, Dingermann T, Marschalek R (2011) The leukemogenic AF4-MLL fusion protein causes P-TEFb kinase activation and altered epigenetic signatures. Leukemia 25: 135-144

Bursen A, Schwabe K, Rüster B, Henschler R, Ruthardt M, Dingermann T, Marschalek R (2010) AF4-MLL is capable of inducing ALL in mice without requirement of MLL-AF4. Blood 115: 3570-3579

Scharf S, Zech J, Bursen A, Schraets D, Oliver PL, Kliem S, Pfitzner E, Gillert E, Dingermann T, Marschalek R (2007) Transcription links to recombination: a gene-internal promoter coincides with the recombination hotspot II of the human MLL gene. Oncogene 26: 1361-1371

Gaussmann A, Wenger T, Eberle I, Bursen A, Bracharz S, Herr I, Dingermann T, Marschalek R (2007) Combined effects of the two reciprocal t(4;11) fusion proteins MLL•AF4 and AF4•MLL confer resistance to apoptosis, cell cycling capacity and growth transformation.Oncogene 26: 3352-3363

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