@phdthesis{Petzoldt2005,
  author    = {Petzoldt, Annemarie Celine},
  title     = {Klinische Bedeutung von immunhistochemischen und zytogenetischen Risikofaktoren beim Mantelzell-Lymphom},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-12383},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2005},
  abstract  = {Um das Risikoprofil beim Mantelzell-Lymphom (MCL) zu identifizieren, wurden morphologische und immunhistochemische Daten von 225 Patienten verglichen. Klinische Daten konnten von 139 Patienten gesammelt werden. Cytogenetische Daten standen von 83 Patienten zur Verf{\"u}gung. Das wichtigste Ergebnis war die H{\"o}he des Proliferationsindex f{\"u}r die individuelle {\"U}berlebensdauer. Vergleichbar mit den Ergebnissen von Rosenwald et al. (Cancer cell, 2/2003, Vol. 3, Seiten 185-197) konnten wir zeigen, daß der Proliferationsindex auch dann mit der {\"U}berlebensdauer korreliert ist, wenn man vier Gruppen mit ansteigendem Proliferationsindex (PI) bildet. Dies beweist die Bedeutung des PI bei Mantelzell-Lymphomen. Zus{\"a}tzlich war eine blastische Zytomorphologie mit einem hohen Mitoseindex, erh{\"o}hten Ki-67 Werten und einer {\"U}berexpression von p53 korreliert. Die Analyse der zytogenetischen Daten ergab folgende h{\"a}ufige Bruchpunkte: 11q13, 14q32, 1p22, 1p32, 6q21 und 1p11. Die h{\"a}ufigsten (partiellen) Trisomien waren: +3, +3q, +3p, +5/5q, +7, +11q, +12q und +X/Xp/Xq, w{\"a}hrend die h{\"a}ufigsten Deletionen in -1p, -6/6q, -8p, -9/9p, -11/11p, -13/13p, 14/14q und -17/17p zu finden waren. Der Bruchpunkt 1q32 war mit blastischer Zytomorphologie assoziiert und Patienten mit Deletionen in 1p, 9/9p und 1q zeigten einen signifikant h{\"o}heren Proliferationsindex als die Kontrollgruppe. Wir konnten zeigen, das Tetraploidie und die Anzahl numerischer Abberationen auf der einen Seite mit blastischer Zytomorphologie und einem hohem Ki-67 Index auf der anderen Seite assoziiert waren. Im Gegensatz dazu gab es keinen Zusammenhang zwischen Ploidie, dem Mitoseindex und einer {\"U}berexpression von p53. Die folgenden Faktoren waren Indikatoren einer ung{\"u}nstigen {\"U}berlebensprognose: Ein Karnofsky Index <80, disseminierter Befall (Ann Arbor III-IV), ein IPI>1, ein H{\"a}moglobin >12,5mg/dl, ein Befall von Leber oder Knochenmark, Leukozytenwerte >10.000, keine Remission oder Progression unter Therapie. Die folgenden Parameter waren mit k{\"u}rzeren {\"U}berlebensdauern assoziiert: >3 Bruchpunkte, >2 strukturelle Abberationen, hohe Mitose- und Ki-67 Indices und eine p53 {\"U}berexpression. Ein Verlust des Y Chromosoms bei M{\"a}nnern war mit einem l{\"a}ngeren {\"U}berleben assoziiert. In der Gruppe mit Langzeit{\"u}berlebern (>7 Jahre) zeigte sich ein geringerer Befall extranodaler Lokalisationen, von Milz und Knochenmark, weniger B-Symptomatik, niedrigere LDH-Werte und weniger disseminierter Befall. Ein niedriger Proliferationsindex war ebenfalls ein wichtiges Kriterium in dieser Gruppe, kein einziger Fall wies eine PI>30\% auf.},
  language  = {de}
}
@phdthesis{Fuhr2023,
  author    = {Fuhr, Viktoria},
  title     = {Target Identification and Validation in Ibrutinib-treated Mantle Cell Lymphoma},
  doi       = {10.25972/OPUS-31059},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-310595},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2023},
  abstract  = {Ibrutinib serves as an efficient second-line therapy in relapsed/refractory mantle cell lymphoma. However, resistance to the BTK inhibitor results in a poor prognosis for patients. Since the mechanisms leading to resistance in initially responding tumor cells are poorly understood, this work aimed to decipher acquired features in ibrutinib-surviving cells of a sensitive mantle cell lymphoma cell line and evaluate these potential therapeutic targets in ibrutinib-treated mantle cell lymphoma. Time-resolved single-cell RNA sequencing was performed to track the transcriptomic evolution of REC-1 cells across 6 and 48 hours of treatment. Single-cell analysis uncovered a subpopulation of REC-1 with potentially greater aggressiveness and survival advantage by benefiting from interaction with the tumor microenvironment. Upregulation of B-cell receptor genes, elevated surface antigen expression of CD52 and metabolic rewiring to higher dependence on oxidative phosphorylation were identified as further potential resistance features of ibrutinib-surviving cells. RNA sequencing after prolonged incubation corroborated the increase in CD52 and oxidative phosphorylation as dominant characteristics of the cells surviving the 4-day treatment, highlighting their potential as therapeutic targets in combination with ibrutinib treatment. Concomitant use of ibrutinib and the oxidative phosphorylation inhibitor IACS-010759 increased toxicity compared to ibrutinib monotherapy due to higher apoptosis and greater inhibition of proliferation. For anti-CD52 therapy, a consecutive approach with ibrutinib pretreatment followed by incubation of surviving cells with a CD52 monoclonal antibody and human serum yielded a synergistic effect, as ibrutinib-surviving mantle cell lymphoma cells were rapidly depleted by complement-dependent cytotoxicity. Regarding the effects on primary tumor cells from mantle cell lymphoma patients, ibrutinib induced upregulation of CD52 in some cases, and increased toxicity of anti-CD52 therapy was observed in ibrutinib-sensitive patient samples after pretreatment with the BTK inhibitor. The likely favorable in vivo efficacy of an anti-CD52 therapy might therefore be restricted to a subgroup of mantle cell lymphoma patients, also in view of the associated side effects. Given the need for new therapeutic options in mantle cell lymphoma to overcome resistance to ibrutinib, this work highlights the potentially beneficial use of an oxidative phosphorylation inhibitor as add-on therapy. In addition, the findings suggest to further assess the value of anti-CD52 therapy as consolidation to ibrutinib in ibrutinib-sensitive patients with elevated CD52 surface levels on tumor cells to target resistant clones and minimize risk of minimal residual disease and relapse.},
  subject      = {B-Zell-Lymphom},
  language  = {en}
}
@article{CarmelaVeglianteRoyoPalomeroetal.2011,
  author    = {Carmela Vegliante, Maria and Royo, Cristina and Palomero, Jara and Salaverria, Itziar and Balint, Balazs and Martin-Guerrero, Idoia and Agirre, Xabier and Lujambio, Amaia and Richter, Julia and Xargay-Torrent, Silvia and Bea, Silvia and Hernandez, Luis and Enjuanes, Anna and Jose Calasanz, Maria and Rosenwald, Andreas and Ott, German and Roman-Gomez, Jose and Prosper, Felipe and Esteller, Manel and Jares, Pedro and Siebert, Reiner and Campo, Elias and Martin-Subero, Jose I. and Amador, Virginia},
  title     = {Epigenetic Activation of SOX11 in Lymphoid Neoplasms by Histone Modifications},
  series = {PLoS ONE},
  volume    = {6},
  journal   = {PLoS ONE},
  number    = {6},
  doi       = {10.1371/journal.pone.0021382},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-135325},
  pages     = {e21382},
  year      = {2011},
  abstract  = {Recent studies have shown aberrant expression of SOX11 in various types of aggressive B-cell neoplasms. To elucidate the molecular mechanisms leading to such deregulation, we performed a comprehensive SOX11 gene expression and epigenetic study in stem cells, normal hematopoietic cells and different lymphoid neoplasms. We observed that SOX11 expression is associated with unmethylated DNA and presence of activating histone marks (H3K9/14Ac and H3K4me3) in embryonic stem cells and some aggressive B-cell neoplasms. In contrast, adult stem cells, normal hematopoietic cells and other lymphoid neoplasms do not express SOX11. Such repression was associated with silencing histone marks H3K9me2 and H3K27me3. The SOX11 promoter of non-malignant cells was consistently unmethylated whereas lymphoid neoplasms with silenced SOX11 tended to acquire DNA hypermethylation. SOX11 silencing in cell lines was reversed by the histone deacetylase inhibitor SAHA but not by the DNA methyltransferase inhibitor AZA. These data indicate that, although DNA hypermethylation of SOX11 is frequent in lymphoid neoplasms, it seems to be functionally inert, as SOX11 is already silenced in the hematopoietic system. In contrast, the pathogenic role of SOX11 is associated with its de novo expression in some aggressive lymphoid malignancies, which is mediated by a shift from inactivating to activating histone modifications.},
  language  = {en}
}