Research groups

Molecular Pediatric Oncology

Group "Molecular Pediatric Oncology"

The research group "Molecular Pediatric Oncology" under the direction of Prof. Dr. med. Andreas Kulozik is particularly concerned with a certain subgroup of leukemias, T-lymphoblastic leukemia (T-ALL). In this disease group, we were able to identify molecular fingerprints that either indicate a particularly good response to the treatment or an unfavorable response.

Within the project of the MMPU (Molecular Medicine Partnership Unit), the researchers work closely with Dr. Jan Korbel at the European Molecular Biology Laboratory (EMBL).

On the one hand, our current projects aim to refine these fingerprints in order to better personalize the treatment in the future. On the other hand, we are interested in the question of how relapsing T-ALLs differ from the initial disease. By this we hope to understand why some patients are resistant to therapy and, most importantly, how we can interfere with these therapy-resistance mechanisms in order to achieve a successful treatment.


Main research aspects

Essential for a successful treatment of malignancies in general and leukemias in particular is to recognize that these diseases, despite their morphological similarity, display a high degree of genetic individuality, indicated by very heterogeneous patterns of acquired somatic mutations. This individuality causes significant differences in response to therapy and, ultimately, treatment success and long-term prognosis.

We have placed our scientific focus on an important subgroup of childhood and adolescent leukemia, T-lymphoblastic leukemia (T-ALL). Patients with a T-ALL who relapse despite well-performed therapy have a particularly poor prognosis.
For this form of leukemia it is, therefore, particularly important to determine valid risk factors at the beginning of treatment. By this, the individual risk of such a relapse can be determined, therapy intensity can be adjusted right at the beginning, and the risk of relapse can be minimized. In addition, modern functional genetic studies allow us to identify individually dysregulated leukemic cell signaling pathways. These findings can provide clues as to which medicines and combinations can be effective in the case of individual leukemia and indicate potential substances for the development of new therapeutic agents.

Deregulation of cellular signaling pathways
Our research results from collaborations with the BFM networks show that the TGF-beta signaling pathway, which is extremely important for the normal regulation of immune cells, is often inactivated in T-ALL. In contrast, the PI3K/Akt signaling pathway that is critical for growth stimulation is often activated. These results, therefore, indicate that, in the case of T-ALLs displaying specific pathway activation, inhibition of the PI3K / AKT signaling pathway could be a new treatment prospect. Our analyzes also show that in children and adolescents with T-ALL, the NOTCH signaling pathway is often deregulated and the tumor suppressor PTEN inactivated.

Currently, we analyze the entire genome of leukemic cells to identify risk factors for relapse. In addition, we want to specify the dysregulated molecular mechanisms that differentiate initially treatment responsive leukemia from relapsing disease of the same patient, as these often react poorly to treatment. We hope that these analyses will help minimize the risk of individual relapse and improve treatment in the case of disease relapse.

Team

  • Prof. Dr. med. Andreas Kulozik (Group leader)
  • Dr. med. Joachim Kunz (Physician scientist)
  • Dr. Paulina Richter-Pechanska (Postdoc)
  • Pia-Elena Frey (MD student)
  • Caroline von Knebel-Doeberitz (MD student)
  • Busra Erarslan (PhD student)

Prof. Dr. med. Andreas Kulozik, PhD

Director "Clinical Pediatric Oncology"

Postal address:
Clinic for Pediatric Oncology, Hematology, and Immunology
Center for Child and Adolescent Medicine
Jutta Mattern
Im Neuenheimer Feld 430
D-69120 Heidelberg
Germany

Selected publications

1. Bandapalli OR, Schuessele S, Kunz JB, Rausch T, Stütz AM, Tal N, Geron I, Gershman N, Izraeli S, Eilers J, Vaezipour N, Kirschner-Schwabe R, Hof J, von Stackelberg A, Schrappe M, Stanulla M, Zimmermann M, Koehler R, Avigad S, Handgretinger R, Frismantas V, Bourquin JP, Bornhauser B, Korbel JO, Muckenthaler MU, Kulozik AE. The activating STAT5B N642H mutation is a common abnormality in pediatric T-cell acute lymphoblastic leukemia and confers a higher risk of relapse. Haematologica. 2014 Oct;99(10):e188-92.

2. Bandapalli O.R., M. Zimmermann, C. Kox, M. Stanulla, M. Schrappe, W.-D. Ludwig, R. Koehler, M.U. Muckenthaler, A.E. Kulozik. NOTCH1 activation clinically antagonizes the unfavorable effect of PTEN inactivation in BFM-treated children with T-ALL. Haematologica 2013 Jan 24

3. Shochat C, Tal N, Bandapalli OR, Palmi C, Ganmore I, Te Kronnie G, Cario G, Cazzaniga G, Kulozik AE, Stanulla M, Schrappe M, Biondi A, Basso G, Bercovich D, Muckenthaler MU, Izraeli S. Gain-of-function mutations in interleukin-7 receptor-alpha (IL7R) in childhood acute lymphoblastic leukemias. Journal of Experimental Medicine 208:901-918. (2011).

4. Kox, C, M. Zimmermann, M. Stanulla, M. S. Leible, M. Schrappe, W.-D. Ludwig, M. Muckenthaler, A.E. Kulozik. The favorable effect of activating NOTCH1 receptor mutations on long-term outcome in T-ALL can be separated from NOTCH pathway activation by FBXW7 loss of function.
Leukemia 24:2005-13 (2010).

5. Kulozik A.E. Taking childhood leukemia personally. Blood 116:4737-8 (2010).