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Clinical Cooperation Unit Pediatric Leukemia

Prof. Dr. Andreas Kulozik

Bone marrow microscopy of pediatric T-ALL
© dkfz.de

Acute lymphoblastic leukemia (ALL) represents the most common malignancy of childhood. While the majority of leukemias in children and adolescents originate from precursor B-cells, precursor T-ALLs represent a particular challenge. Although 80-90% of affected patients can be cured from their primary disease on modern treatment protocols, relapses have a particularly poor prognosis thus indicating a fundamental difference in the biology between these different stages of disease evolution in this type of leukemia. Therefore, it is our goal to understand the biology of pediatric T-ALL and translate this knowledge into better treatment. By performing targeted genetic and genomic analyses our previous research identified genetic changes impacting on treatment response and prognosis (Breit et al. 2006, Kox et al. 2010, Bandapalli et al. 2014, Richter-Pechanska et al. 2017). In our current research we focus on high risk genetic markers that hallmark relapsed T-ALLs and that may already be present in small subclones at the time of primary disease. As mutations in epigenetic regulators are common in T-ALL, we further focus on epigenetic differences of T-ALLs compared to normal thymic precursors and have found that the chromatin accessibility of T-ALLs, including those with mature immunophenotypes, resemble the most immature normal thymic precursor cells and identified surprising transcriptional profiles in epigenetically defined subtypes of T-ALL (Richter-Pechanska et al. 2018, Erarslan-Uysal et al. 2020).
Complete list of references

In our future work we will remain focused on the question of how the biology of T-ALL relapses explains the exquisite treatment resistance in this challenging phase of disease evolution in this type of leukemia. An important cornerstone of our future work will be the observation that T-ALL relapses can be biologically distinguished by their leukemic cell of origin. While 'type 1' relapse derives from the major clone prevalent at the time of the primary leukemia, 'type 2' relapse originates from a pre-leukemic ancestor that only exists in a small subclone of the primary leukemia (Kunz et al. 2015). By comparing primary and the two types of T-ALL relapses in the same patients by multi-omic longitudinal analyses we are now aiming at identifying the type-specific functional pathways responsible for the clinical aggressiveness of the relapsed disease. Further we will aim at functionally validating pathways that emerged from our previous genomic and epigenomic analyses.

Contact

Prof. Dr. Andreas Kulozik
Pediatric Leukemia (A400)
Deutsches Krebsforschungszentrum
Im Neuenheimer Feld 350
69120 Heidelberg
Tel: +49 6221 564500

Selected Publications

  • Erarslan-Uysal B, Kunz JB, Rausch T, Richter-Pechanska P, van Belzen IA, Frismantas V, Bornhauser B, Ordoñez-Rueada D, Paulsen M, Benes V, Stanulla M, Schrappe M, Cario G, Escherich G, Bakharevich K, Kirschner-Schwabe R, Eckert C, Loukanov T, Gorenflo M, Waszak SM, Bourquin JP, Muckenthaler MU, Korbel JO, Kulozik AE (2020). Chromatin accessibility landscape of pediatric T-lymphoblastic leukemia and human T-cell precursors. Erarslan EMBO Mol Med. e12104. doi: 10.15252/emmm.202012104. PMID: 32755029
  • Richter-Pechanska 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 (2018). PDX models recapitulate the genetic and epigenetic landscape of pediatric T-cell leukemia. EMBO Mol Med e9443. doi: 10.15252/emmm.201809443. PMID: 30389682
  • Richter-Pechanska 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 (2017). Identification of a genetically defined ultra-high-risk group in relapsed pediatric T-lymphoblastic leukemia. Blood Cancer J.:e523. doi: 10.1038/bcj.2017.3. PMID: 28157215
  • 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 (2015). Pediatric T-cell lymphoblastic leukemia evolves into relapse by clonal selection, acquisition of mutations and promoter hypomethylation. Haematologica 100:1442-50. doi: 10.3324/haematol.2015.129692. PMID: 26294725
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