These disorders result from a mutation(s) of DNA within a single pluripotential marrow hematopoietic stem cell or very early multipotential progenitor cell. Mutations disturb the function of the gene product(s).
Overt cytogenetic abnormalities can be found in 50% to 80% of cases of acute myelogenous leukemia (AML) in cytogenetic laboratories (see Williams Hematology, 9th ed, Chap. 13, Figure 13–3).
— Translocations (eg, t(15;17); t(8;21)) and inversions of chromosomes (eg, inv16) can result in the expression of fusion genes that encode fusion proteins that are oncogenic.
— Overexpression or underexpression of genes that encode molecules critical to the control of cell growth, or programmed cell death, often within signal transduction pathways or involving transcription factors occur.
— Deletions of all or part of a chromosome (eg, -5, 5q-, -7, or -7q) or duplication of all or part of a chromosome may be evident (eg, trisomy 8).
An early multipotential hematopoietic cell undergoes clonal expansion but retains the ability to differentiate and mature, albeit with varying degrees of pathologic features, into various blood cell lineages (Figure 40–1).
The result is often abnormal blood cell concentrations (either above or below normal), abnormal blood cell structure and function; the abnormalities may range from minimal to severe.
Resulting disease phenotypes are numerous and varied because of the eight myeloid and three lymphoid differentiation lineages from a multipotential hematopoietic stem cell.
Neoplasms that result can be grouped, somewhat arbitrarily, by the degree of loss of differentiation and maturation potential and by the rate of disease progression.
Most patients can be grouped into the classic diagnostic designations listed in Table 40–1.
Leukemic hematopoiesis in acute myelogenous leukemia (AML). The malignant process evolves from a single mutant multipotential cell (possibly a lymphohematopoietic pluripotential cell). This cell, on the basis of a sequence of somatic mutations, becomes a leukemia stem cell with a growth advantage in relationship to normal pluripotential stem cells. Whether all cases of acute myelogenous leukemia originate in the pluripotential stem cell pool is still under study. This cell is capable of multivariate commitment to leukemic erythroid, granulocytic, monocytic, and megakaryocytic progenitors. In most cases, granulocytic and/or monocytic commitment predominates, and myeloblasts and promonocytes or their immediate derivatives are the dominant cell types. Leukemic blast cells accumulate in the marrow. The leukemic blast cells may become amitotic (sterile) and undergo programmed cell death, may stop dividing for prolonged periods (blasts in G0) but have the potential to reenter the mitotic cycle, or may divide and then undergo varying degrees of maturation. Maturation may lead to mature “leukemic” cells, such as red cells, segmented neutrophils, monocytes, or platelets. A severe block in maturation is characteristic of AML, whereas a high proportion of leukemic primitive multipotential cells mature into terminally differentiated cells of all lineages in patients with chronic myelogenous leukemia. The disturbance in differentiation and maturation in myelogenous leukemia is quantitative, thus many patterns are possible. At least ...
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