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LEUKEMIC STEM CELLS
Pancytopenia is typical and results in part from the physical replacement of normal marrow elements by immature cells. Following replacement of the bone marrow, the abnormal cells spill into the circulation and infiltrate other organs. The various types of leukemia are identified primarily by the identity of the target cell that undergoes transformation. When the cancer develops in the lymphocytes (lymphoid lineage), it is called lymphocytic leukemia, while cancer of the granulocytes or monocytes (myeloid lineage) is described as myelogenous leukemia. The rate of disease progression is an additional feature used for classification. In chronic leukemias, the immature hematopoietic progenitors (colloquially referred to as blasts) accumulate slowly and continue to form functional hematopoietic cells; because of this, disease progression is slow. On the other hand, in acute leukemias, the progenitors proliferate rapidly, resulting in blast accumulation, decreased turnover of mature hematopoietic cells, and rapid disease progression. Normal and leukemic severe compromised immune deficiency (SCID)-repopulating cells (SRCs) coexist in the bone marrow and peripheral blood from patients in the chronic phase, whereas a dominance of leukemic SRCs is evident in blast crisis.[23] Thus, the main classes of leukemia include (1) chronic myeloid leukemia, (2) acute myeloid leukemia, (3) chronic lymphocytic leukemia, (4) acute lymphoblastic/lymphocytic leukemia. Chronic Myeloid Leukemia (CML) CML is a malignant, clonal myeloproliferative disorder, affecting the myeloid, erythroid, and megakaryocytic blood elements, that accounts for 15 to 20 % of all cases of leukemia. This was the first hematological malignancy to be identified in association with a specific chromosomal abnormality[24] and involves a translocation between chromosomes 9 and 22, now recognized as the Philadelphia chromosome (Ph1). The molecular consequence of Ph1 is the fusion of the ABL gene (chromosome 9) to the BCR (breakpoint cluster region on chromosome 22) sequences, giving rise to a chimeric BCR-ABL gene. The product of this fusion functions as a constitutively activated tyrosine kinase and is involved in an endless list of pathways found to be altered in CML (including transforming functions). Consequently, the BCR-ABL kinase becomes a molecular target for drug design as well as monitoring therapeutic efficacies. Existing therapies for CML include the use of busulfan, hydroxyurea, interferon-ι, imanitib, or allogenic stem cell transplantation. In early chronic-phase CML, the apoptosis and differentiation pathways are often intact; however, the disease invariably progresses from a chronic phase to an accelerated acute phase, also referred to as blast phase or blast crisis. This is accompanied by a loss of capacity of the transformed cell clone for terminal differentiation and is characterized by massive blast and promyelocyte counts, leukocytosis, and splenomegaly, along with acquisition of additional cytogenetic abnormalities in addition to the Ph1 abnormality. Although initially it was believed that CML arises as a consequence of the clonal expansion of HSCs that express the BCR-ABL fusion gene,[25 – 29] it is now realized that progression to blast crisis is associated with expansion of the myeloid progenitor fraction, which consists mainly of GMPs that acquire some degree of self-renewal capacity rather than