Chapter 40: Classification and Clinical Manifestations of the Clonal Myeloid Disorders

PATHOGENESIS

• 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.