Despite several recent advancements in the treatment of B lymphoproliferative disorders, still a considerable number of lymphoma cases either cannot be cured or become incurable when relapsing. This issue reflects the need for better and more effective therapies that can be designed once novel pathogenic mechanisms have been designed and suitable preclinical models have been established. Therefore, aim of this thesis was to understand the molecular mechanisms leading to mature B lymphoid malignancies by using different mouse models, in order to identify novel potential therapeutic targets and obtain useful models for preclinical studies. In chapter 2 we show the establishment of a new xenograft model obtained by injecting the CLL cell line MEC1 into immunodeficient Rag2‒/‒gammac‒/‒ mice. This model resembles the aggressive form of human CLL and is conceivably useful to test the efficacy of new therapeutic agents. In chapter 3 we show that HS1 is involved in the trafficking and homing of leukemic B cells and that its deficiency is responsible for an earlier onset of the disease and a reduced survival in the Emu-TCL1 mouse model of CLL. The same animal model was used to investigate the role of TLR pathway in CLL. In chapter 4 we report that the absence of TIR8 accelerates the appearance of the disease and favors the progression into an aggressive form characterized by the accumulation of “prolymphocytoid” cells. Finally in chapter 5 we demonstrate that mice lacking the negative regulator SIGLEC-G are susceptible to B cell lymphoma development with age indicating that the downregulation of SIGLEC10 may be involved in the malignant transformation of human B lymphocytes.

(2012). B lymphoid malignancies: insights from mouse models. (Tesi di dottorato, Università degli Studi di Milano-Bicocca, 2012).

B lymphoid malignancies: insights from mouse models

SIMONETTI, GIORGIA
2012-03-26

Abstract

Despite several recent advancements in the treatment of B lymphoproliferative disorders, still a considerable number of lymphoma cases either cannot be cured or become incurable when relapsing. This issue reflects the need for better and more effective therapies that can be designed once novel pathogenic mechanisms have been designed and suitable preclinical models have been established. Therefore, aim of this thesis was to understand the molecular mechanisms leading to mature B lymphoid malignancies by using different mouse models, in order to identify novel potential therapeutic targets and obtain useful models for preclinical studies. In chapter 2 we show the establishment of a new xenograft model obtained by injecting the CLL cell line MEC1 into immunodeficient Rag2‒/‒gammac‒/‒ mice. This model resembles the aggressive form of human CLL and is conceivably useful to test the efficacy of new therapeutic agents. In chapter 3 we show that HS1 is involved in the trafficking and homing of leukemic B cells and that its deficiency is responsible for an earlier onset of the disease and a reduced survival in the Emu-TCL1 mouse model of CLL. The same animal model was used to investigate the role of TLR pathway in CLL. In chapter 4 we report that the absence of TIR8 accelerates the appearance of the disease and favors the progression into an aggressive form characterized by the accumulation of “prolymphocytoid” cells. Finally in chapter 5 we demonstrate that mice lacking the negative regulator SIGLEC-G are susceptible to B cell lymphoma development with age indicating that the downregulation of SIGLEC10 may be involved in the malignant transformation of human B lymphocytes.
GHIA, PAOLO
B cell lymphoma, Chronic Lymphocytic Leukemia, B lymphocytes, mouse models
MED/06 - ONCOLOGIA MEDICA
English
Scuola di Dottorato in Medicina Traslazionale e Molecolare
MEDICINA TRASLAZIONALE E MOLECOLARE (DIMET) - 45R
24
2010/2011
(2012). B lymphoid malignancies: insights from mouse models. (Tesi di dottorato, Università degli Studi di Milano-Bicocca, 2012).
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/10281/30033
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