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)
  • 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. Ex vivo drug response profiling detects recurrent sensitivity patterns in drug-resistant acute lymphoblastic leukemia. Frismantas V, Dobay MP, Rinaldi A, Tchinda J, Dunn SH, Kunz J, Richter-Pechanska P, Marovca B, Pail O, Jenni S, Diaz-Flores E, Chang BH, Brown TJ, Collins RH, Uhrig S, Balasubramanian GP, Bandapalli OR, Higi S, Eugster S, Voegeli P, Delorenzi M, Cario G, Loh ML, Schrappe M, Stanulla M, Kulozik AE, Muckenthaler MU, Saha V, Irving JA, Meisel R, Radimerski T, Von Stackelberg A, Eckert C, Tyner JW, Horvath P, Bornhauser BC, Bourquin JP. Blood. 2017 Mar 16;129(11):e26-e37. doi: 10.1182/blood-2016-09-738070. Epub 2017 Jan 25. PMID: 28122742 Free PMC article.

2. Identification of a genetically defined ultra-high-risk group in relapsed pediatric T-lymphoblastic leukemia. Richter-Pechańska P, Kunz JB, Hof J, Zimmermann M, Rausch T, Bandapalli OR, Orlova E, Scapinello G, Sagi JC, Stanulla M, Schrappe M, Cario G, Kirschner-Schwabe R, Eckert C, Benes V, Korbel JO, Muckenthaler MU, Kulozik AE. Blood Cancer J. 2017 Feb 3;7(2):e523. doi: 10.1038/bcj.2017.3. PMID: 28157215 Free PMC article.

3. Treatment of patients with relapsed or refractory CD19+ lymphoid disease with T lymphocytes transduced by RV-SFG.CD19.CD28.4-1BBzeta retroviral vector: a unicentre phase I/II clinical trial protocol. Schubert ML, Schmitt A, Sellner L, Neuber B, Kunz J, Wuchter P, Kunz A, Gern U, Michels B, Hofmann S, Hückelhoven-Krauss A, Kulozik A, Ho AD, Müller-Tidow C, Dreger P, Schmitt M. BMJ Open. 2019 May 19;9(5):e026644. doi: 10.1136/bmjopen-2018-026644. PMID: 31110096 Free PMC article. Clinical Trial.

4. PDX models recapitulate the genetic and epigenetic landscape of pediatric T-cell leukemia. Richter-Pechańska P, Kunz JB, Bornhauser B, von Knebel Doeberitz C, Rausch T, Erarslan-Uysal B, Assenov Y, Frismantas V, Marovca B, Waszak SM, Zimmermann M, Seemann J, Happich M, Stanulla M, Schrappe M, Cario G, Escherich G, Bakharevich K, Kirschner-Schwabe R, Eckert C, Muckenthaler MU, Korbel JO, Bourquin JP, Kulozik AE. EMBO Mol Med. 2018 Dec;10(12):e9443. doi: 10.15252/emmm.201809443. PMID: 30389682 Free PMC article.

5. MAP3K7 is recurrently deleted in pediatric T-lymphoblastic leukemia and affects cell proliferation independently of NF-κB. Cordas Dos Santos DM, Eilers J, Sosa Vizcaino A, Orlova E, Zimmermann M, Stanulla M, Schrappe M, Börner K, Grimm D, Muckenthaler MU, Kulozik AE, Kunz JB. BMC Cancer. 2018 Jun 18;18(1):663. doi: 10.1186/s12885-018-4525-0. PMID: 29914415 Free PMC article. Clinical Trial.

6. PTEN abnormalities predict poor outcome in children with T-cell acute lymphoblastic leukemia treated according to ALL IC-BFM protocols. Szarzyńska-Zawadzka B, Kunz JB, Sędek Ł, Kosmalska M, Zdon K, Biecek P, Bandapalli OR, Kraszewska-Hamilton M, Jaksik R, Drobna M, Kowalczyk JR, Szczepański T, Van Vlierberghe P, Kulozik AE, Witt M, Dawidowska M. Am J Hematol. 2019 Apr;94(4):E93-E96. doi: 10.1002/ajh.25396. Epub 2019 Jan 24. PMID: 30614545 Clinical Trial. No abstract available.

7. Expression of CD56 defines a distinct subgroup in childhood T-ALL with inferior outcome. Results of the ALL-BFM 2000 trial. Fuhrmann S, Schabath R, Möricke A, Zimmermann M, Kunz JB, Kulozik AE, Ludwig WD, Schrappe M, Karawajew L, Ratei R. Br J Haematol. 2018 Oct;183(1):96-103. doi: 10.1111/bjh.15503. Epub 2018 Jul 20. PMID: 30028023 Clinical Trial.

8. Genomic profiling of Acute lymphoblastic leukemia in ataxia telangiectasia patients reveals tight link between ATM mutations and chromothripsis. Ratnaparkhe M, Hlevnjak M, Kolb T, Jauch A, Maass KK, Devens F, Rode A, Hovestadt V, Korshunov A, Pastorczak A, Mlynarski W, Sungalee S, Korbel J, Hoell J, Fischer U, Milde T, Kramm C, Nathrath M, Chrzanowska K, Tausch E, Takagi M, Taga T, Constantini S, Loeffen J, Meijerink J, Zielen S, Gohring G, Schlegelberger B, Maass E, Siebert R, Kunz J, Kulozik AE, Worst B, Jones DT, Pfister SM, Zapatka M, Lichter P, Ernst A. Leukemia. 2017 Oct;31(10):2048-2056. doi: 10.1038/leu.2017.55. Epub 2017 Feb 15. PMID: 28196983

9. Single-cell analysis of structural variations and complex rearrangements with tri-channel processing. Sanders AD, Meiers S, Ghareghani M, Porubsky D, Jeong H, van Vliet MACC, Rausch T, Richter-Pechańska P, Kunz JB, Jenni S, Bolognini D, Longo GMC, Raeder B, Kinanen V, Zimmermann J, Benes V, Schrappe M, Mardin BR, Kulozik AE, Bornhauser B, Bourquin JP, Marschall T, Korbel JO. Nat Biotechnol. 2020 Mar;38(3):343-354. doi: 10.1038/s41587-019-0366-x. Epub 2019 Dec 23. PMID: 31873213

10. NOTCH1 mutation, TP53 alteration and myeloid antigen expression predict outcome heterogeneity in children with first relapse of T-cell acute lymphoblastic leukemia. Hof J, Kox C, Groeneveld-Krentz S, Bandapalli OR, Karawajew L, Schedel K, Kunz JB, Eckert C, Ludwig WD, Ratei R, Rhein P, Henze G, Muckenthaler MU, Kulozik AE, von Stackelberg A, Kirschner-Schwabe R. Haematologica. 2017 Jul;102(7):e249-e252. doi: 10.3324/haematol.2016.157792. Epub 2017 Mar 30. PMID: 28360149 Free PMC article. No abstract available.

11. Pediatric T-cell lymphoblastic leukemia evolves into relapse by clonal selection, acquisition of mutations and promoter hypomethylation. Kunz JB, Rausch T, Bandapalli OR, Eilers J, Pechanska P, Schuessele S, Assenov Y, Stütz AM, Kirschner-Schwabe R, Hof J, Eckert C, von Stackelberg A, Schrappe M, Stanulla M, Koehler R, Avigad S, Elitzur S, Handgretinger R, Benes V, Weischenfeldt J, Korbel JO, Muckenthaler MU, Kulozik AE. Haematologica. 2015 Nov;100(11):1442-50. doi: 10.3324/haematol.2015.129692. Epub 2015 Aug 20. PMID: 26294725 Free PMC article. Clinical Trial.