TY - CHAP M1 - Book, Section TI - Classification and Clinical Manifestations of the Clonal Myeloid Disorders A1 - Lichtman, Marshall A. A2 - Kaushansky, Kenneth A2 - Lichtman, Marshall A. A2 - Prchal, Josef T. A2 - Levi, Marcel M. A2 - Press, Oliver W. A2 - Burns, Linda J. A2 - Caligiuri, Michael PY - 2015 T2 - Williams Hematology, 9e AB - SUMMARYThe clonal myeloid neoplasms result from acquired driver and cooperating mutations within a multipotential marrow cell, or sometimes, perhaps, a stem cell. Translocations, inversions, duplications (e.g., trisomy, tetrasomy), and deletions of chromosomes can result in (1) the expression of fusion genes that encode oncogenic fusion proteins or (2) 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 also identified relevant somatic mutations in cases without an overt 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 a modest effect on longevity to severe cytopenias and death in days, if the disorder is untreated. The somatically mutated multipotential cell from which the clonal expansion of neoplastic hematopoietic cells derives acquires the features of a stem cell and retains the ability, with varying degrees of imperfection, 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 are common, such as thrombocytosis as a feature of polycythemia vera, essential thrombocythemia, primary myelofibrosis, and chronic myelogenous leukemia. The clonal (refractory) anemias may be accompanied by functionally insignificant or very severe neutropenia or thrombocytopenia or sometimes thrombocytosis. These findings reflect the unpredictable expression of the mutant multipotential hematopoietic cell’s differentiation and 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, responsible for 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 chronic myelogenous leukemia and t(15;17)(q22;q21) (PML-RARα) with acute promyelocytic leukemia. However, most patients can be grouped into a classic diagnostic designations listed in Table 83–1. The mutant stem cells that maintain the clone may undergo further somatic mutations over time resulting in a more aggressive phenotype, notably acute leukemia, usually of the myeloid type. An important feature of the clonal myeloid diseases is the potentially reversible suppression of normal (polyclonal) stem cells by the clonally expanded neoplastic cells. The coexistence of normal polyclonal stem cells and their competition with the neoplastic clone forms the basis for the remission-relapse pattern seen in acute myelogenous leukemia after intensive chemotherapy and the reappearance of polyclonal, normal hematopoiesis in patients with chronic myelogenous leukemia after tyrosine kinase BCR-ABL inhibitor therapy. This ... SN - PB - McGraw-Hill Education CY - New York, NY Y2 - 2024/03/29 UR - accessmedicine.mhmedical.com/content.aspx?aid=1121097987 ER -