Chapter 41: 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).

• Cytogenetic abnormalities can be found in 50% to 80% of cases of acute myelogenous leukemia (AML) (see Williams Hematology, 10th ed, Chap. 11, Table 11–2).

  — 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, occurs.

  — 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).

  — Specific cytogenetic abnormalities and gene mutations and their correlates, if any, with specific myeloid neoplasms are described in Chaps. 41, 42, 43, 44, 45, 46, 47, 48.

• 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 41–1). In most myeloid neoplasms, mutated clone suppresses normal hematopoietic stem cells from division, and they become dormant.

• The result is often abnormal blood cell concentrations (either above or below normal) and 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 major myeloid and four major 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 41–1.