Mechanisms of Leukemogenesis

Mechanisms of Leukemogenesis

PD Dr. rer. nat Daniel Mertens

Department of Internal Medicine III

University of Ulm

Albert-Einstein-Allee 23

89081 Ulm

Germany

E-Mail: daniel.mertens[at]uniklinik-ulm.de, d.mertens[at]dkfz.de

Homepage: www.mertens-lab.de

Project Leader

PD Dr. rer. nat. Daniel Mertens

Lab Members (Ulm)

Bianca Brakel

Karin Müller

Lab Members (Heidelberg)

Dr. rer. nat. Cordula Tschuch

Leticia Serra

Melanie Ruppel

Suzin Choi

We are interested in the molecular mechanisms that cause leukemias and lymphomas. The scope of our research projects ranges from the elucidation of an epigenetic suppressor mechanism to the characterization of leukemogenic signal transduction pathways in the malignant cells.
 

(A)
Elucidation of the tumor suppressor mechanism localized in chromosomal band 13q14.3

A variety of human malignancies show loss of a critical region in chromosomal band 13q14.3 that harbors a tumor suppressor mechanism. In more than 50% of patients suffering from B-cell chronic lymphocytic leukemia (B-CLL), the most common leukemia of the western world, this region is deleted. Despite extensive efforts from a number of labs, the molecular nature of this mechanism has proven elusive. The region contains long non-coding RNA genes, micro-RNA genes and multicistronic transcripts. We have recently been able to show a complex epigenetic regulatory mechanism in this region which involves DNA-methylation, asynchronous replication timing and monoallelic expression. This epigenetic mechanism can explain some of the genetic peculiarities observed in patients. What we are currently doing is to elucidate the intricacies of the regulatory mechanism characterize the molecular function of the candidate tumor suppressor genes in the critical region. With the insights gained, we hope to impact not only on the diagnosis of B-CLL patients but also open new avenues for treatment strategies.
 

(B)
How does the microenvironment support leukemic cells?

Malignant cells of patients suffering from B-cell chronic lymphocytic leukemia (B-CLL) accumulate in the lymphatic organs and peripheral blood and finally result in the failure of the immune system. However, if the malignant cells are cultured in vitro, they rapidly undergo apoptosis unless they are supported by non-malignant stroma cells. This suggests an intimate interaction of the leukemia cells with their microenvironment and an essential dependence on survival signals from the supporting cells. In a systematic approach, we want to characterize the delicate interplay of these anti-apoptotic signals which have been discovered to date. Even though each of these signals prolongs the life of CLL cells in vitro, none of them can alone substitute the anti-apoptotic effect that the stromal cells have on the leukemic cells in vitro. If we are able to describe this crucial balance of supporting signals and identify its central nodes, these could be directly targeted in the patients using low but effective doses of compounds, some of which are already clinically established.

• Max-Eder Programm der Deutschen Krebshilfe
• Medizinische Fakultät Universität Ulm, Abteilung Innere Medizin III
• Helmholtz Nachwuchsgruppenförderung (Juniorgruppe am DKFZ)
• EU Marie Curie Training Network
• Deutsche José Carreras Leukämie-Stiftung

(a comprehensive list is available at www.mertens-lab.de)
 

Mertens, D., S. Wolf, C. Tschuch, C. Mund, D. Kienle, S. Ohl, P. Schroeter, F. Lyko, H. Döhner, S. Stilgenbauer and P. Lichter (2006). "Allelic silencing at the tumor-suppressor locus 13q14.3 suggests an epigenetic tumor-suppressor mechanism."
Proc Natl Acad Sci U S A 103(20): 7741-6. IF 10.452

Mertens, D., S. Wolf, P. Schroeter, C. Schaffner, H. Döhner, S. Stilgenbauer and P. Lichter (2002). "Down-regulation of candidate tumor suppressor genes within chromosome band 13q14.3 is independent of the DNA methylation pattern in B-cell chronic lymphocytic leukemia."
Blood 99(11): 4116-21. IF 9.782

Wolf, S., D. Mertens, C. Schaffner, C. Korz, H. Döhner, S. Stilgenbauer and P. Lichter (2001). "B-cell neoplasia associated gene with multiple splicing (BCMS): the candidate B-CLL gene on 13q14 comprises more than 560 kb covering all critical regions."
Hum Mol Genet 10(12): 1275-85. IF 7.801

Mertens, D., S. Wolf, L. Bullinger, S. Ohl, C. Schaffner, H. Döhner, S. Stilgenbauer and P. Lichter (2000). "BCMSUN, a candidate gene for B-cell chronic lymphocytic leukemia and mantle-cell lymphoma, has an independently expressed homolog on 1p22- p31, BCMSUN-like."
Int J Cancer 88(5): 692-7. IF 4.416

• Prof. Dr. rer. nat. P. Lichter, DKFZ, Heidelberg
• Prof. Dr. med. Stephan Stilgenbauer
• Dr.rer.nat. Martina Seiffert, DKFZ, Heidelberg
• PD. Dr.rer.nat. Karsten Rippe, DKFZ, Heidelberg
• Dr.rer.nat. Axel Szabowski, DKFZ, Heidelberg
• Dr.rer.nat. Andreas Ladurner, EMBL, Heidelberg
• Dipl. Stat. A. Benner, DKFZ, Heidelberg