Role of Pre-B Cell Receptor Signaling Molecules in B Cell Differentiation and Tumor Suppression Ta, T.B.V. 2010-12-15 Doctoral Thesis

In this thesis I aimed to unravel the molecular mechanism involved in the origin of acute lymphoblastic leukemia (ALL). This malignant disease is characterized by oncogenic transformation of progenitors of the B cell lineage in the bone marrow. To study the basis of this disease I have used a mouse model: mice lacking the signaling protein Slp65. This is an important transducer of signals at the precursor (pre)-B cell stage, which reflects a crucial checkpoint for proliferation and differentiation in the bone marrow. Although Slp65-deficient mice do not show increased sizes of any B-lineage subpopulation in the bone marrow, a substantial portion of mice develop ALL. To understand why these Slp65-deficient cells are prone to oncogenic transformation, knowledge on the function of Slp65 in pre-B cells is required. In the introduction to my thesis, I first describe the development of B lymphocytes and in particular I focus on the pre-B cell stage. We are interested in the functions depending on the signaling protein Slp65, this involves cellular maturation and differentiation, regulation of V(D)J recombination and termination of proliferation. This introduction will help to understand the basis of the mechanisms possibly involved in the malignant transformation of Slp65-deficient pre-B cells.
http://repub.eur.nl/res/pub/22989/Ta_Full.pdf