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KiTZ research on leukemia
The research group leukemia, headed by Prof. Dr. Andreas Kulozik, is particularly concerned with a subgroup of leukemias, the T-lymphoblastic leukemias (T-ALL). In this group of diseases, we have been able to identify molecular fingerprints that signal either a particularly good response to treatment or an unfavorable response. The researchers are working closely with Dr. Jan Korbel at the European Molecular Biology Laboratory (EMBL) as part of the MMPU (Molecular Medicine Partnership Unit).
Our current projects aim, on the one hand, to refine these fingerprints to such an extent that we can better personalize treatment in the future. On the other hand, we are interested in the question of how T-ALLs in relapse differ from the initial disease. In this way, we want to understand why therapy resistance occurs in some patients and, above all, how we can disrupt these therapy resistance mechanisms in order to still achieve successful treatment.
Individualized leukemia therapy
An essential basis for successful treatment of malignancies in general and leukemias in particular is the recognition that, despite their morphological similarity, these diseases exhibit a high degree of genetic individuality due to very different patterns of acquired somatic mutations. This individuality implies substantial differences in response to therapy and ultimately in treatment success and long-term prognosis.
We have placed our scientific focus on an important subset of childhood and adolescent leukemias, T-lymphoblastic leukemia (T-ALL). Patients with T-ALL who relapse despite well-administered therapy have a particularly poor prognosis.
It is therefore particularly important in this form of leukemia to determine valid risk factors at the beginning of treatment. In this way, the individual risk of such a relapse can be determined, the intensity of therapy can be targeted accordingly from the outset, and the risk of relapse can be minimized. In addition, modern functional genetic studies allow us to identify the individually dysregulated signaling pathways in the leukemia cell. These findings can provide clues as to which drugs and which combinations may be effective in individual leukemia and which compounds bring potential for new drug development.
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, which is crucial for growth stimulation, is frequently activated. These results therefore indicate that inhibition of the PI3K/AKT pathway specifically in T-ALLs with PI3K/AKT activation may be a novel treatment perspective. Our analyses further show that in children and adolescents with T-ALL, the NOTCH signaling pathway is often deregulated as well as the tumor suppressor PTEN is inactivated.
Currently, we are using whole genome analyses of leukemia cells to identify risk factors for the occurrence of relapse. In addition, we aim to specify the dysregulated molecular mechanisms that distinguish leukemia that initially responds well to treatment in the initial disease from leukemia in the same patient that then usually responds poorly to treatment in relapse. We hope that these analyses will contribute to minimizing the individual risk of relapse and to improving the treatment of relapses that have occurred.
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.
