TCR Translocations at the Normal-malignant T Cell Interface

Hematopoiesis is the process leading to production and maturation of peripheral blood cells. All blood cells are derived from hematopoietic stem cells (HSCs) which reside in hematopoietic organs. In mammals, the site of hematopoiesis changes during development, which is sequentially taking place in different organs starting with primitive erythrocytes in the yolk sac, the aorta-gonad mesonephros (AGM) region, the fetal lever, and finally the bone marrow (BM) during adulthood. Blood cells are short-lived, and with a daily demand for more than a billion new hematopoietic cells, a continuous replenishment of progenitor cells committed to specific hematopoietic lineages is required. HSCs are at the top of the hematopoietic hierarchy, and are the only source of progenitors. HSCs comprise 0.005-0.01% of the bone marrow, and their unique properties, i.e. the ability of self-renewal and multi-lineage differentiation potential in combination with a specific stem cell microenvironment/ niche, enable these cells to sustain the hematopoietic system. These cells differentiate into progenitor cells, either into common lymphoid progenitors (CLP) or common myeloid progenitors (CMP), which in due course differentiate into mature blood cells, providing cells to the myeloid or lymphoid system respectively 6. CLPs carry the potential to give rise to B cells, T cells (via the thymus) and NK cells, whereas CMPs have the potential to differentiate into erythrocytes, megakaryocytes, macrophages, and granulocytes. Dendritic cells can arise from both progenitor types. The process of hematopoietic lineage determination is tightly regulated by the BM microenvironment’s extrinsic factors, such as growth factors and cytokines mediated by cell-cell interactions, which sustain survival and proliferation of committed cells. Equally important in determining cell fate are the lineage- and cell-type-specific gene expression signatures (intrinsic factors). These signatures are based on the up and down regulation of transcription factors apparently regulated by the epigenetic-micro RNAs regulatory circuit. The strict regulation of both extrinsic and intrinsic signals is of utmost importance, as deregulation of the expression of these factors could result in hematopoietic malignancies such as leukemia or lymphoma. Such deregulation of gene expression is usually caused by irreversible molecular-cytogenetic changes introduced into the genomic DNA sequence. These changes can be caused by mutations, translocations and deletions concerning genes involved in cell cycle, differentiation, proliferation, and self-renewal processes. During the last decade it has become evident that, next to genetic aberrations, epigenetic alterations can also contribute to tumorigenesis, for example through gene silencing due to aberrant methylation. .

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