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The clonal myeloid disorders result from acquired mutations within a multipotential marrow cell or very early progenitor cell. The chromosomal alteration resulting in the primary mutation sometimes is evident when cytogenetic analysis is performed. Translocations, inversions, and deletions of chromosomes can result in (1) the expression of fusion genes that encode fusion proteins that are oncogenic or (2) the overexpression or underexpression of genes that encode molecules critical to the control of cell growth, programmed cell death, or other regulatory pathways. Duplication of chromosomes, such as trisomy, also results in deregulated cellular behavior. Gene and miRNA (microribonucleic acid) expression profiling has also identified potentially leukemogenic gene mutations in cases without a cytogenetic abnormality. The different mutations may result in phenotypes that range from mild impairment of the steady-state levels of blood cells, insignificant functional impairment of cells, and little consequence on longevity to severe cytopenias and death in days, if the disorder is untreated. The somatically mutated (neoplastic) multipotential cell from which the clonal expansion of hematopoietic cells derives retains the ability, with various degrees of imperfection, to differentiate and mature into each blood cell lineage. The particular syndrome may have altered blood cell concentrations, structure, and function, and minimal to severe effects on a particular blood cell lineage. The effect on any one lineage occurs in an unpredictable way, even in subjects within the same category of disease. The resulting phenotypes are, therefore, innumerable and varied. In polycythemia vera or thrombocythemia, maturation of progenitors results in cells nearly normal in appearance and function, but their level in the blood is excessive. Moreover, overlapping features are common, such as thrombocytosis as a feature of polycythemia vera, essential thrombocythemia, primary myelofibrosis, or chronic myelogenous leukemia. The clonal anemias may be accompanied by insignificant or very severe neutropenia or thrombocytopenia or sometimes thrombocytosis. These findings reflect the unpredictable expression of the mutant multipotential cell’s differentiation capabilities for which the genetic explanations are largely unknown. Tight relationships between the cytogenetic alteration and the phenotype occur in only a few circumstances, and even these are imperfect, for example, translocation (t) (9;22)(q34;q11)(BCR-ABL;p210) with chronic myelogenous leukemia and t(15;17)(q22;q21) (PML-RARα) with acute promyelocytic leukemia. However, most patients can be grouped into the classic diagnostic designations listed in Table 85–1. An important feature of the clonal myeloid diseases is the potentially reversible suppression of normal (polyclonal) stem cells by the clonally expanded cells. This coexistence and competition forms the basis for the remission-relapse pattern seen in acute myelogenous leukemia after intensive chemotherapy and for the reappearance of polyclonal, normal hematopoiesis in many patients with chronic myelogenous leukemia after tyrosine kinase inhibitor therapy.

Table 85–1. Neoplastic (Clonal) Myeloid Disorders

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