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Pathogenesis

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**Driver mutations in AML tend to fall into four functional categories:**

**Transcription factor mutations** that interfere with normal myeloid differentiation.
- For example, the two most common chromosomal rearrangements, t(8;21) and inv(16), disrupt the RUNX1 and CBFB genes, respectively. These two genes encode polypeptides that bind one another to form a RUNX1/CBFB transcription factor that is required for normal hematopoiesis. The t(8;21) and the inv(16) create chimeric genes encoding fusion proteins that interfere with the function of RUNX1/CBFB and block the matura- tion of myeloid cells. Another important example is found in acute promyelocytic leukemia, a distinctive subtype of AML associated with the t(15;17). The t(15;17) creates a fusion gene encoding a chimeric protein consisting of the retinoic acid receptor-α (RARα) and a portion of a protein called PML. As discussed in Chapter 7, this fusion protein interferes with the terminal differentiation of granulocytes, an effect that can be overcome by treatment with all-trans-retinoic acid and arsenic trioxide.

**Mutation of signaling proteins that result in constitutive activation of pro-growth/survival pathways.**
- For example, AMLs with the t(15;17) also frequently have activating mutations in FLT3, a receptor tyrosine kinase that transmits signals that mimic normal growth factor signal- ing, thereby increasing cellular proliferation and survival. The combination of PML-RARα and activated FLT3 is a potent inducer of AML in mice, whereas expression of PML-RARα alone is only weakly leukemogenic. Mutations in a large number of other genes involved in pro-growth signaling, such as RAS, also occur in subsets of AML.

**Mutation of genes that regulate or maintain the “epigenome.” **
- Some of these mutations lead to abnormal DNA methylation patterns or involve members of the cohesin family, proteins that regulate the three-dimensional organization of chromatin in the nucleus. Another group of mutations involving the enzymes IDH1 or IDH2 result in the acquisition of a new enzymatic activity that produces the oncometabolite 2-hydroxyglutarate
- IDH inhibitors are effective in treating IDH-mutated forms of AML. The precise mechanism by which disturbances of the epigenome contribute to the develop- ment of AML remains to be determined, but presumably they lead to alterations in gene expression that contribute to the acquisition of one or more cancer hallmarks.
•** Mutation of TP53 or genes that regulate p53. **
- With increasingly routine sequencing of AML genomes, it has become apparent that AMLs with mutations that impair p53 function have distinctive clinicopathologic features, including associations with complex karyotype, marked dysplasia, and particularly poor prognosis due to resistance to standard therapies.

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Immunophenotype. Because it can be difficult to distinguish myeloblasts and lymphoblasts morphologically, the diagnosis of AML is confirmed by performing stains for myeloid- specific antigens (Fig. 13.30B and C).

Cytogenetics. Cytogenetic analysis has a central role in the classification of AML. Karyotypic aberrations are detected in 50% to 70% of cases with standard techniques and in approximately 90% of cases using special high-resolution banding. Particular chromosomal abnormalities correlate with certain clinical features. AML arising de novo in younger adults is commonly associated with balanced chromosomal translocations, particularly t(8;21), inv(16), and t(15;17). In contrast, AML following MDS or exposure to DNA-damaging agents (such as chemotherapy or radiation therapy) often has deletions or monosomies involving chromosomes 5 and 7 and usually lack chromosomal translocations. The exception to this rule is AML occurring after treatment with topoisomerase II inhibitors, which is strongly associated with translocations involving the KTM2A gene on chromosome 11q23. AML in older adults also is more likely to be associated with “bad” aberrations, such as deletions of chromosomes 5q and 7q and complex karyotypic abnormalities, features that are associated with mutations that impair p53 function.