Chapter 45: The Acute Myelogenous Leukemias

INTRODUCTION

• Acute myelogenous leukemia (AML) is a malignancy originating in the lymphohematopoietic stem cell or a closely related multipotential hematopoietic cell.

• It is characterized by clonal proliferation of abnormal blast cells in the marrow and impaired production of normal blood cells, resulting in anemia; thrombocytopenia; and low, normal, or high white cell counts depending on the concentration of leukemic cells in the blood.

• AML occurs in nine morphologic (phenotypic) variants, each with characteristic cytologic, genetic, and sometimes clinical features.

• It has been found to have innumerable (more than 150) mutated genetic driver and cooperating oncogenes.

ETIOLOGY AND PATHOGENESIS

• The chronic clonal myeloid diseases may undergo clonal evolution to AML (eg, polycythemia vera, Chap. 41; essential thrombocythemia, Chap. 42; myelofibrosis, Chap. 47; myelodysplastic syndromes, Chap. 44; the chronic myelogenous leukemias, Chap. 46).

• AML develops with increased frequency in patients with certain congenital (Down syndrome) or inherited abnormalities (eg, Fanconi anemia, familial platelet syndrome) as shown in Table 45–1.

• Nonsyndromic, familial occurrence, indicating an inherited predisposition gene, has been documented but is very uncommon.

• Most cases arise de novo and are associated with either acquired cytogenetic changes, including translocation, inversions, deletions, and other forms of aneuploidy or pseudodiploidy. These changes lead to the mutation of proto-oncogenes and the formation of oncogenes. Frequently, the latter encode mutant transcription factors resulting in disruption of cell signaling pathways that cause malignant transformation.

• In the absence of chromosome abnormalities, one can identify specific gene mutations that account for the disruption in normal hematopoiesis and the establishment of a leukemic clone.

• Thus, AML results from a series of somatic mutations in a multipotential hematopoietic cell or, in a small proportion of cases, a more differentiated, lineage restricted progenitor cell. In acute promyelocytic leukemia (APL), some cases of monocytic leukemia, and some young persons with other forms of AML, the disease may originate in a mutated granulocytic-monocytic progenitor cell that is transformed into a leukemic stem cell.

• The mutations resulting in AML disrupt stem cell differentiation and unilineage progenitor maturation, regulation of proliferation, and of cell survival (apoptosis) in varying combinations. This complexity results in many phenotypes.