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The myeloid neoplasms result from acquired driver and cooperating mutations within a marrow stem cell, or a closely related multipotential cell. Translocations, inversions, duplications (eg, trisomy, tetrasomy), and deletions of chromosomes can result in (a) the expression of fusion genes that encode oncogenic fusion proteins or (b) the overexpression or underexpression of genes that encode molecules critical to the control of cell growth, programmed cell death, cell differentiation and maturation, or other regulatory pathways. Gene sequencing has identified relevant somatic mutations in cases without an overt cytogenetic abnormality. If the disorder is untreated, the mutations, depending on their specificity, cooperativity, and interactions, may result in phenotypes that range from no apparent clinically detectable abnormality of blood cells, mild impairment of the steady-state levels of blood cells, morphology indistinguishable from normal by light microscopy, insignificant functional impairment of cells, and a modest, if any, effect on longevity to, on the other end of the spectrum, severe cytopenias, accumulation of leukemic blast cells, and death in days to weeks. The somatically mutated stem cell from which the clonal expansion of neoplastic hematopoietic cells derives retains the features of a stem cell (“leukemic” stem cell) and, thus, retains the ability, with varying degrees of imperfection from slight to profound, to differentiate and mature into each blood cell lineage. A particular disease in this spectrum of phenotypes may have altered blood cell concentrations and cell structural and functional abnormalities, and these may range from minimal to severe, involving several blood cell lineages. 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 essential thrombocythemia, differentiation and subsequent maturation of unipotential progenitor cells results in blood cells nearly normal in appearance and function, but their level in the blood is excessive. Moreover, overlapping features among the clonal myeloid disorders are common, such as thrombocytosis as an integral feature of essential thrombocythemia, a common feature of polycythemia vera, and a feature of some cases of primary myelofibrosis and chronic myelogenous leukemia (CML). The clonal cytopenias and oligoblastic myelogenous leukemias, commonly referred to as myelodysplastic syndromes, although they are overt and often florid neoplasias and not dysplasias, may be accompanied by functionally insignificant or very severe neutropenia or thrombocytopenia or sometimes thrombocytosis and low blast counts (<2%) or elevated blast counts (>2%) and by convention up to 19% marrow myeloblasts. These variable findings reflect the unpredictable expression of the mutant hematopoietic stem cell’s differentiation ability and its derivative progenitor cells’ variable maturation capabilities for which the genetic explanations are not well defined. The mutant cell of origin takes on the features of a (leukemic) stem cell, capable of self-renewal, thereby sustaining the disease process. Tight relationships between the genetic alteration and phenotype occur in only a few circumstances, and even these are imperfect, for example, t(9;22)(q34;q11)(BCR-ABL1;p210) with CML and t(15;17)(q22;q21)(PML-RARα) ...

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