DYSREGULATION OF HEMATOPOIESIS IN LEUKEMIA
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have been established as guidelines in disease subtyping. Chromosomal alterations may either be inherited, or induced by such external factors as alkylating drugs, ionizing radiations, and chemicals, and are realized to be an underlying feature in the emergence of a LSC, as they often mediate alterations in the structure and/or regulation of cellular oncogenes. Retroviral infections are also believed to be capable of leading to leukemogenesis via an insertional mutagenesis of oncogenes.[16] LSC identity is thus largely dictated by the nature of the oncogenic events and how these events perturb the essential processes of self-renewal, proliferation, differentiation, and survival. The genetic lesions in LSCs result in a block of differentiation (maturation arrest) that allows cells belonging to a certain clone not only to continue proliferation and to resist apoptosis, but also to accumulate in large numbers, which is not a feature associated with normal hematopoietic cellular hierarchies. Increasing evidence now indicates that three key biological changes affect the development of leukemic clones: (1) an increased probability of differentiation defects at the level of the most primitive LSCs or early progenitors, (2) an increased turnover rate of the leukemic progenitors at all stages of differentiation, and (3) an increased ability to survive under conditions of growth factor deprivation. Such a model accounts for the long latent period for the development of certain leukemias, such as chronic myeloid leukemia (CML), as well as suggesting why stem cells may persist in large numbers but still fail to compete in contributing to the daily output of mature blood cells in patients with disease.[17] Another requirement for HSCs and LSCs is the ability to avoid telomere shortening through the action of the telomerase complex.[18;19] Telomerase activity is also repressed during differentiation of maturation-sensitive human tumor cell lines but not in resistant human tumor cell lines.[20] Thus, under normal conditions, an inverse relationship between the degree of differentiation and telomerase activity exists and is regulated in an HSC by restricting the number of cell divisions that it can undergo in a human lifetime. The most important component of the telomerase complex is human telomerase reverse transcriptase (hTERT), which is often overexpressed in tumor cells. Alternatively, telomerase activity and hTERT mRNA expression may not be increased significantly, but variations in mRNA splicing may play a significant role in determining the overall length of telomeres and thereby the functional hTERT levels that restrict telomere shortening despite a rapid turnover of cells, and lengthen the life span of the transformed clone.[21] 2.2.3 Types of Leukemia Leukemia thus represents a heterogeneous group of monoclonal diseases that arise from hematopoietic stem and progenitor cells in the bone marrow or other hematopoietic organs.[22] As described above, the underlying causes for clonal expansion are poorly understood but definitely involve several genetic and epigenetic changes. All these events culminate in an imbalance created by the accumulation of large numbers of cells of an individual lineage. In addition, the abnormal cells may secrete factors that perturb the homeostatic mechanisms and inhibit normal hematopoiesis, thus generating the symptoms of leukemia.