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Pediatric Oncology and Hematology

One of the scariest sentences horrifying parents probably is: "Your child has cancer." One of the most reassuring is: "A fatal disease has become curable by GPOH-based treatment protocols”.

Cancer in minors is rare in Europe and accounts for only 1% of all childhood diseases. While approximately 480,000 adults are diagnosed with malignancies in Germany annually, this affects only 1,800 patients aged under 18 years (ratio 267:1). Facing this rarity, networks of pediatric oncologists conducting multi-center, cooperative, standardized clinical trials in Germany were started in the 1970ies with the primary goal to obtain valid data from large patient cohorts with the same type of pediatric cancer. Today more than 35 treatment protocols are designed by the Society of Pediatric Oncology and Hematology (Gesellschaft für Pädiatrische Onkologie und Hämatologie, GPOH) and continuously optimized based on the most current scientific knowledge obtained by previous trials. Overall, these clinical trials accomplish the concept of comparatively testing effectiveness rather via multimodal treatment concepts than by studying single drugs. The major goal is to further increase cure rates and also to reduce long term side-effects, and thus to improve the quantity and the quality of cure. As of today by this approach the 5-year-survival rates have increased to 75% - 90% for the majority of childhood cancer patients. The Division of Pediatric Oncology and Hematology (POH) at the University Hospital Carl Gustav Carus Dresden (Head: Meinolf Suttorp) proudly participates in the GPOH network presently comprising 58 German treatment centers for POH diseases and contributes to the landscape of trials with expertise in pediatric chronic myeloid leukemia (CML) since the year 1994.
 
CML is very rare in Germany, only 15-20 patients younger than 18 years are diagnosed annually.  Meinolf Suttorp is chairing trials on pediatric CML for over 20 years. As in adults, treatment by modern tyrosine kinase inhibitors (TKI, e.g. imatinib) has now “operationally cured” this leukemia deferring stem cell transplantation (SCT) towards a 2nd or 3rd line approach. However, pediatric CML differs in some aspects form CML in adults [1, 4, 5] and specific side effects like impaired bone growth [3] and endocrine alterations are observed in children [5] thus challenging the use of TKI in pediatric patients [2,5].

Pediatric Oncology

A. Originalpublikationen

1. An autochthonous mouse model of Myd88- and BCL2-driven diffuse large B cell lymphoma reveals actionable molecular vulnerabilities . Ruth Flümann, Tim Rehkämper, Pascal Nieper, Pauline Pfeiffer, Alessandra Holzem, Sebastian Klein, Sanil Bhatia, Moritz Kochanek, Ilmars Kisis, Benedikt Pelzer, Heinz Ahlert, Julia Hauer, Alexandra da Palma Guerreiro, Jeremy Ryan, Maurice Reimann, Arina Riabinska, Janica Wiederstein, Marcus Krüger, Martina Deckert, Janine Altmüller, Andreas Klatt, Lukas Frenzel, Laura Pasqualucci, Wendy Beguelin, Ari Melnick, Sandrine Sander, Manuel Montesinos-Rongen, Anna Brunn, Philipp Lohneis, Reinhard Büttner, Hamid Kashkar, Arndt Borkhardt, Anthony Letai, Thorsten Persigehl, Martin Peifer, Clemens Schmitt, Hans Reinhardt, and Gero Knittel Blood Cancer Discovery 2020 in press.

2. An intact gut microbiome protects genetically predisposed mice against leukemia.  Vicente-Dueñas C, Janssen S, Oldenburg M, Auer F, González-Herrero I, Casado-García A, Isidro-Hernández M, Raboso-Gallego J, Westhoff P, Pandyra AA, Hein D, Gössling KL, Alonso-López D, De Las Rivas J, Bhatia S, García-Criado FJ, García-Cenador MB, Weber APM, Köhrer K, Hauer J, Fischer U, Sánchez-García I, Borkhardt A.Vicente-Dueñas C, et al Blood. 2020 Oct 29;136(18):2003-2017.

3. Multicomponent Synthesis, Binding Mode, and Structure-Activity Relationship of Selective Histone Deacetylase 6 (HDAC6) Inhibitors with Bifurcated Capping Groups. Reßing N, Sönnichsen M, Osko JD, Schöler A, Schliehe-Diecks J, Skerhut A, Borkhardt A, Hauer J, Kassack MU, Christianson DW, Bhatia S, Hansen FK.Reßing N, et al. J Med Chem. 2020 Sep 24;63(18):10339-10351.

4. Regional BCG vaccination policy in former East- and West Germany may impact on both severity of SARS-CoV-2 and incidence of childhood leukemia. Hauer J, Fischer U, Auer F, Borkhardt A.Hauer J, et al. Among authors: borkhardt a. Leukemia. 2020 Aug;34(8):2217-2219. doi: 10.1038/s41375-020-0871-4.

5. Infectious stimuli promote malignant B-cell acute lymphoblastic leukemia in the absence of AID. Rodríguez-Hernández G, Opitz FV, Delgado P, Walter C, Álvarez-Prado ÁF, González-Herrero I, Auer F, Fischer U, Janssen S, Bartenhagen C, Raboso-Gallego J, Casado-García A, Orfao A, Blanco O, Alonso-López D, Rivas JL, Tena-Dávila SG, Müschen M, Dugas M, Criado FJG, Cenador MBG, Vicente-Dueñas C, Hauer J*, Ramiro AR*, Sanchez-Garcia I*, Borkhardt A*. Nat Commun. 2019 Dec 5;10(1):5563. *contributed equally

6. JAK2p.G571S in B-cell precursor acute lymphoblastic leukemia: a synergizing germline suszeptibility. Lin M, Nebral K, Gertzen CGW, Ganmore I, Haas OA, Bhatia S, Fischer U, Kuhlen M, Gohlke H, Izraeli S, Trka J, Hu J, Borkhardt A, Hauer J*, Auer F*.
Leukemia. 2019 Apr 9.. *contributed equally

7. Discovery oft he First-in-Class Dual Histone Deacetylase-Proteasome Inhibitor. Bhatia S, Krieger V, Groll M, Osko JD, Reßing N, Ahlert H, Borkhardt A, Kurz T, Christianson DW, Hauer J*, Hansen FK*.
J Med Chem. 2018 Nov 21;61(22):10299-10309. *contributed equally

8. Lmo2 expression defines tumor cell identity during T-cell leukemogenesis.
García-Ramírez I, Bhatia S, Rodríguez-Hernández G, González-Herrero I, Walter C, González de Tena-Dávila S, Parvin S, Haas O, Woessmann W, Stanulla M, Schrappe M, Dugas M, Natkunam Y, Orfao A, Domínguez V, Pintado B, Blanco O, Alonso-López D, De Las Rivas J, Martín-Lorenzo A, Jiménez R, García Criado FJ, García Cenador MB, Lossos IS, Vicente-Dueñas C*, Borkhardt A*, Hauer J*, Sánchez-García I*.
EMBO J. 2018 Jul 13;37(14). *contributed equally

9. Targeting HSP90 dimerization via the C terminus is effective in imatinib-resistant CML and lacks the heat shock response.
Bhatia S, Diedrich D, Frieg B, Ahlert H, Stein S, Bopp B, Lang F, Zang T, Kröger T, Ernst T, Kögler G, Krieg A, Lüdeke S, Kunkel H, Rodrigues Moita AJ, Kassack MU, Marquardt V, Opitz FV, Oldenburg M, Remke M, Babor F, Grez M, Hochhaus A, Borkhardt A, Groth G, Nagel-Steger L, Jose J, Kurz T, Gohlke H, Hansen FK*, Hauer J*.
Blood. 2018 Jul 19;132(3):307-320. *contributed equally

10. Loss of Pax5 Exploits Sca1-BCR-ABLp190 Susceptibility to Confer the Metabolic Shift Essential for pB-ALL.
Martín-Lorenzo A, Auer F, Chan LN, García-Ramírez I, González-Herrero I, Rodríguez-Hernández G, Bartenhagen C, Dugas M, Gombert M, Ginzel S, Blanco O, Orfao A, Alonso-López D, Rivas JL, García-Cenador MB, García-Criado FJ, Müschen M, Sánchez-García I*, Borkhardt A*, Vicente-Dueñas C*, Hauer J*.
Cancer Res. 2018 May 15;78(10):2669-2679 *contributed equally

11. Activation-induced cytidine deaminase prevents pro-B cell acute lymphoblastic leukemia by functioning as a negative regulator in Rag1 deficient pro-B cells.
Auer F, Ingenhag D, Pinkert S, Kracker S, Hacein-Bey-Abina S, Cavazzana M, Gombert M, Martin-Lorenzo A, Lin MH, Vicente-Dueñas C, Sánchez-García I, Borkhardt A, Hauer J.
Oncotarget. 2017 Sep 7;8(44):75797-75807.

12. Infection Exposure Promotes ETV6-RUNX1 Precursor B-cell Leukemia via Impaired H3K4 Demethylases.
Rodríguez-Hernández G*, Hauer J*, Martín-Lorenzo A*, Schäfer D, Bartenhagen C, García-Ramírez I, Auer F, González-Herrero I, Ruiz-Roca L, Gombert M, Okpanyi V, Fischer U, Chen C, Dugas M, Bhatia S, Linka RM, Garcia-Suquia M, Rascón-Trincado MV, Garcia-Sanchez A, Blanco O, García-Cenador MB, García-Criado FJ, Cobaleda C, Alonso-López D, De Las Rivas J, Müschen M, Vicente-Dueñas C, Sánchez-García I, Borkhardt A.
Cancer Res. 2017 Aug 15;77(16):4365-4377 *contributed equally

13. Childhood cancer predisposition syndromes-A concise review and recommendations by the Cancer Predisposition Working Group of the Society for Pediatric Oncology and Hematology.
Ripperger T, Bielack SS, Borkhardt A, Brecht IB, Burkhardt B, Calaminus G, Debatin KM, Deubzer H, Dirksen U, Eckert C, Eggert A, Erlacher M, Fleischhack G, Frühwald MC, Gnekow A, Goehring G, Graf N, Hanenberg H, Hauer J, Hero B, Hettmer S, von Hoff K, Horstmann M, Hoyer J, Illig T, Kaatsch P, Kappler R, Kerl K, Klingebiel T, Kontny U, Kordes U, Körholz D, Koscielniak E, Kramm CM, Kuhlen M, Kulozik AE, Lamottke B, Leuschner I, Lohmann DR, Meinhardt A, Metzler M, Meyer LH, Moser O, Nathrath M, Niemeyer CM, Nustede R, Pajtler KW, Paret C, Rasche M, Reinhardt D, Rieß O, Russo A, Rutkowski S, Schlegelberger B, Schneider D, Schneppenheim R, Schrappe M, Schroeder C, von Schweinitz D, Simon T, Sparber-Sauer M, Spix C, Stanulla M, Steinemann D, Strahm B, Temming P, Thomay K, von Bueren AO, Vorwerk P, Witt O, Wlodarski M, Wössmann W, Zenker M, Zimmermann S, Pfister SM, Kratz CP.
Am J Med Genet A. 2017 Apr;173(4):1017-1037

14. Infection as a cause of childhood leukemia: virus detection employing whole genome sequencing.
Bartenhagen C, Fischer U, Korn K, Pfister SM, Gombert M, Chen C, Okpanyi V, Hauer J, Rinaldi A, Bourquin JP, Eckert C, Hu J, Ensser A, Dugas M, Borkhardt A.
Haematologica. 2017 May;102(5):e179-e183.

15. Infection causes childhood leukemia.
Hauer J, Martín-Lorenzo A, Sánchez-García I.
Aging (Albany NY). 2015 Sep;7(9):607-8.

16. Infection exposure is a causal factor in B-precursor acute lymphoblastic leukemia as a result of Pax5 inherited susceptibility.
Martin-Lorenzo A*, Hauer J*, Vicente-Duenas C*, Auer F, Gonzalez-Herrero I, Garcia-Ramirez I, Ginzel S, Thiele R, Constantinescu SN Prof, Bartenhagen C, Dugas M, Gombert M, Schafer D, Blanco O, Mayado A, Orfao A, Alonso-Lopez D, De Las Rivas J, Cobaleda C, Garcia-Cenador MB, Garcia-Criado FJ, Sanchez-Garcia I, Borkhardt A.
Cancer Discov. 2015 Dec;5(12):1328-43. doi: 10.1158/2159-8290.CD-15-0892
* and # contributed equally. (highlighted in Nature and Nature Cancer Reviews)

17. Variable correction of Artemis deficiency by I-Sce1-meganuclease-assisted homologous recombination in murine hematopoietic stem cell.
Julie Rivière, Julia Hauer, Laurent Poirot, Julien Brochet, Philippe Souque, Karine Mollier, Agnes Gouble, Pierre Charneau, Alain Fischer, Frédéric Pâques, Jean-Pierre de Villartay, and M Cavazzana
Gene Ther. 2014 May;21(5):529-32.

18. Recombination-activating gene 1 (Rag1)-deficient mice with severe combined immunodeficiency treated with lentiviral gene therapy demonstrate autoimmune Omenn-like syndrome.
van Til NP, Sarwari R, Visser TP, Hauer J, Lagresle-Peyrou C, van der Velden G, Malshetty V, Cortes P, Jollet A, Danos O, Cassani B, Zhang F, Thrasher AJ, Fontana E, Poliani PL, Cavazzana M, Verstegen MM, Villa A, Wagemaker G.
J Allergy Clin Immunol. 2013 Dec 8. pii: S0091-6749(13)01560-1. doi: 10.1016/j.jaci.2013.10.009.

19. Inherited susceptibility to pre B-ALL caused by germline transmission of PAX5 c.547G>A.
Auer F, Rüschendorf F, Gombert M, Husemann P, Ginzel S, Izraeli S, Harit M, Weintraub M, Weinstein OY, Lerer I, Stepensky P, Borkhardt A, Hauer J.
Leukemia. 2013 Nov 29. doi: 10.1038/leu.2013.363.

20. Frequent and sex-biased deletion of SLX4IP by illegitimate V(D)J-mediated recombination in childhood acute lymphoblastic leukemia.
Meissner B, Bartram T, Eckert C, Trka J, Panzer-Grümayer R, Hermanova I, Ellinghaus E, Franke A, Möricke A, Schrauder A, Teigler-Schlegel A, Dörge P, von Stackelberg A, Basso G, Bartram CR, Kirschner-Schwabe R, Bornhäuser B, Bourquin JP, Cazzaniga G, Hauer J, Attarbaschi A, Izraeli S, Zaliova M, Cario G, Zimmermann M, Avigad S, Sokalska-Duhme M, Metzler M, Schrappe M, Koehler R, Te Kronnie G, Stanulla M.
Hum Mol Genet. 2014 Feb 1;23(3):590-601. doi: 10.1093/hmg/ddt447.

21. Anti-leukaemic activity of a novel haploidentical-transplantation approach employing unmanipulated bone marrow followed by CD6-depleted peripheral blood stem cells in children with refractory/relapsed acute leukaemia.
Schuster FR, Meisel R, Führer M, Reuther S, Hauer J, Tischer J, Feuchtinger T, Laws HJ, Kolb HJ, Borkhardt A.
Br J Haematol. 2013 Sep;162(6):802-7. doi: 10.1111/bjh.12455.

22. Homeobox protein HB9 binds to the prostaglandin E receptor 2 promoter and inhibits intracellular cAMP mobilization in leukemic cells.
Wildenhain S, Ingenhag D, Ruckert C, Degistirici O, Dugas M, Meisel R, Hauer J*, Borkhardt A*.
J Biol Chem. J Biol Chem. 2012 Nov 23;287(48):40703-12. * contributes equally

23. Loss of p19Arf in a Rag1-/- B-precursor population initiates acute B-lymphoblastic leukaemia
Julia Hauer, Charles Mullighan, Estelle Morillon, Gary Wang, Julie Bruneau, Nicole Brousse, Marc Lelorc`h, Serge Romana, Amine Boudil, Daniela Tiedau, Sven Kracker, Frederick D Bushmann , Arndt Borkhardt, Alain Fischer, Salima Hacein Bey, Marina Cavazzana-Calvo.
Blood. 2011 Jul 21;118(3):544-53.

24. Research recommendations toward a better understanding of the causes of childhood leukaemia Q1
G Ziegelberger, C Baum, A Borkhardt, C Cobaleda, C Dasenbrock, A Dehos, B Grosche, J Hauer, S Hornhardt, T Jung,T Kammertoens, I Lagroye, H Lehrach, T, Lightfoot, MP Little, C Rossig, I Sanchez-Garcia, M Schrappe, J Schuez, S Shalapour, R Slany, M Stanulla and W Weiss
Blood Cancer Journal (2010) 1, eXX; doi:10.1038/bcj.2010.1

25. Expression of cell-cell interacting genes distinguishes HLXB9/TEL from MLL-positive childhood acute myeloid leukaemia.
Wildenhain S, Ruckert C, Röttgers S, Harbott J, Ludwig WD, Schuster FR, Beldjord K, Binder V, Slany R, Hauer J*, Borkhardt A*.
Leukaemia. 2010 Sep;24(9):1657-60. * contributes equally

26. Ten Years of Gene Therapy for X-linked Severe Combined Immunodeficiency
Hacein-Bey-Abina S, Hauer J, Lim A, Picard C,  Wang G.P, Berry C.C, Martinache C, Rieux-Laucat F,  Latour S, Belohradsky B.H, Leiva L, Sorensen R, Casanova J.L, Blanche S, Durandy A, Bushman FD, Fischer A,  Cavazzana-Calvo M 
N Engl J Med. 2010 Jul 22;363(4):355-64.

27. A self-inactivating lentiviral vector for SCID-X1 gene therapy that does not activate LMO2 expression in human T cells
Sheng Zhou, Disha Mody, Suk See DeRavin, Julia Hauer, Taihe Lu, Zhijun Ma, Salima Hacein-Bey Abina, John T. Gray, Michael R Greene, Marina Cavazzana-Calvo, Harry L. Malech, and Brian P. Sorrentino
Blood. 2010 Aug 12;116(6):900-8. May 10

28. Insertional oncogenesis in 4 patients after retrovirus-mediated gene therapy of SCID-X1.
Hacein-Bey-Abina S, Garrigue A, Wang GP, Soulier J, Lim A, Morillon E, Clappier E, Caccavelli L, Delabesse E, Beldjord K, Asnafi V, MacIntyre E, Dal Cortivo L, Radford I, Brousse N, Sigaux F, Moshous D, Hauer J, Borkhardt A, Belohradsky BH, Wintergerst U, Velez MC, Leiva L, Sorensen R, Wulffraat N, Blanche S, Bushman FD, Fischer A, Cavazzana-Calvo M.
J Clin Invest. 2008 Sep;118(9):3132-42.

29. Stable and functional lymphoid reconstitution in artemis-deficient mice following lentiviral artemis gene transfer into haematopoietic stem cells.
Benjelloun F, Garrigue A, Demerens-de Chappedelaine C, Soulas-Sprauel P, Malassis-Séris M, Stockholm D, Hauer J, Blondeau J, Rivière J, Lim A, Le Lorc'h M, Romana S, Brousse N, Pâques F, Galy A, Charneau P, Fischer A, de Villartay JP, Cavazzana-Calvo M.
Mol Ther. 2008 Aug;16(8):1490-9.  

30. Graft versus leukaemia effect after haploidentical HSCT in a MLL-negative infant AML with HLXB9/ETV6 rearrangement.
Hauer J, Tosi S, Schuster FR, Harbott J, Kolb HJ, Borkhardt A.
Pediatr Blood Cancer. 2008 Apr;50(4):921-3.

31. Effective treatment of kaposiform hemangioendotheliomas associated with Kasabach-Merritt phenomenon using four-drug regimen.
Hauer J, Graubner U, Konstantopoulos N, Schmidt S, Pfluger T, Schmid I.
Pediatr Blood Cancer. 2007 Nov;49(6):852-4.

32. TNF receptor (TNFR)-associated factor (TRAF) 3 serves as an inhibitor of TRAF2/5-mediated activation of the noncanonical NF-kappaB pathway by TRAF-binding TNFRs.
Hauer J, Püschner S, Ramakrishnan P, Simon U, Bongers M, Federle C, Engelmann H.
Proc Natl Acad Sci U S A. 2005 Feb 22;102(8):2874-9.  

B. Reviews

1. Modeling the process of childhood ETV6-RUNX1 B-cell leukemias.
Rodríguez-Hernández G, Schäfer D, Gavilán A, Vicente-Dueñas C, Hauer JBorkhardt A, Sánchez-García I.
Oncotarget. 2017 Sep 27;8(60):102674-102680

2. Epigenetic Priming in Cancer Initiation.
Vicente-Dueñas C, Hauer J, Cobaleda C, Borkhardt A, Sánchez-García I.
Trends Cancer. 2018 Jun;4(6):408-417.

3. Mouse models for pre-clinical drug testing in leukemia.
Bhatia S, Daschkey S, Lang F, Borkhardt AHauer J.
Expert Opin Drug Discov. 2016 Nov;11(11):1081-1091.

4. GEMMs addressing Pax5 loss-of-function in childhood pB-ALL.
Auer F, Ingenhag D, Bhatia S, Enczmann J, Cobaleda C, Sanchez-Garcia I, Borkhardt A, Hauer J.
Eur J Med Genet. 2016 Mar;59(3):166-72. doi: 10.1016/j.ejmg.2015.11.009. Epub 2015 Nov 26. Review.

5. Genetically engineered mouse models of human B-cell precursor leukemias.
Hauer J, Borkhardt A, Sánchez-García I, Cobaleda C.
Cell Cycle. 2014;13(18):2836-46. doi: 10.4161/15384101.2014.949137. Review

6. Tumoral stem cell reprogramming as a driver of cancer: Theory, biological models, implications in cancer therapy.
Vicente-Dueñas C, Hauer J, Ruiz-Roca L, Ingenhag D, Rodríguez-Meira A, Auer F, Borkhardt A, Sánchez-García I.
Semin Cancer Biol. 2015 Jun;32:3-9. doi: 10.1016/j.semcancer.2014.02.001.