AML primarily affects older adults; the median age is 50 years. It is very heterogeneous, as discussed later. The clinical signs and symptoms closely resemble those produced by ALL and usually are related to the replacement of normal marrow elements by leukemic blasts. Fatigue, pallor, abnormal bleeding, and infections are common in newly diagnosed patients, who typically present within a few weeks of the onset of symptoms. Splenomegaly and lymphadenopathy generally are less prominent than in ALL, but on rare occasions AML mimics a lymphoma by manifesting as a discrete tissue mass (a so-called “granulocytic sarcoma”). The diagnosis and classification of AML are based on morphologic, histochemical, immunophenotypic, and karyotypic findings. Of these, the karyotype is most predictive of outcome.
Most AMLs harbor mutations in genes encoding transcription factors that are required for normal myeloid cell differentiation. These mutations interfere with the differentiation of early myeloid cells, leading to the accumulation of myeloid precursors (blasts) in the marrow. Of particular interest is the (15;17) translocation in acute promyelocytic leukemia, which results in the fusion of the retinoic acid receptor α (RARA) gene on chromosome 17 and the PML gene on chromosome 15. The chimeric gene produces a PML/RARA fusion protein that blocks myeloid differentiationat the promyelocyticstage, probablyinpart by inhibiting the function of normal retinoic acid receptors. Remarkably, pharmacologic doses of all-trans retinoic acid (ATRA), an analogue of vitamin A (Chapter 7), overcome this block and induce the neoplastic promyelocytes to differentiate into neutrophils rapidly. Because neutrophils die after an average life span of 6 hours, ATRA treatment rapidly clears the tumor. The effect is very specific; AMLs without trans-locations involving RARA do not respond to ATRA. More recently, it has been noted that the combination of ATRA and arsenic trioxide, a salt that induces the degradation of the PML/RARA fusion protein, is even more effective than ATRA alone, producing cures in more than 80% of patients. This is an important example of a highly effective therapy targeted at a tumor-specific molecular defect.
Other work using mice has shown that the mutations in transcription factors found in AML are not sufficient to cause the disease. Putative collaborating mutations in several other tyrosine kinase genes and in the RAS gene have been detected.
Sequencing of the AML genomes also has identified frequent mutations in genes that directly impact the epigenome, suggesting that epigenetic alterations have a central role in AML. For example, about 15% to 20% of AMLs are associated with mutations in isocitrate dehydrogenase (IDH). In such tumors, an “oncometabolite” synthesized by the mutated IDH protein blocks the function of enzymes that regulate the epigenome and interferes with myeloid cell differentiation (discussed in Chapter 6). Inhibitors of mutant IDH prevent the production of the oncometabolite and often produce remissions in this particular molecular subtype of AML.
MORPHOLOGYBydefinition,inAMLmyeloidblastsorpromyelocytesmakeupmorethan20%ofthebonemarrowcellularity.Myeloblasts (precursorsofgranulocytes)havedelicatenuclearchromatin,threetofivenucleoli,andfineazurophiliccytoplasmicgranules(
Fig.12.26 ).Auer rods, distinctivered-stainingrodlikestructures,maybepresentinmyeloblastsormoredifferentiatedcells;theyareparticularlynumerousinacutepromyelocyticleukemia(