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After studying this chapter, you should understand:

  • The pathogenic role of mutations in genes encoding transcription factors and signaling molecules in acute leukemia.

  • The diagnostic and prognostic role of immunophenotyping, cytogenetics, and molecular genetics in acute leukemia.

  • The general approach to treatment of patients with acute leukemia and the associated short-term complications.

  • The unique role of “differentiating” agents in the treatment of acute promyelocytic leukemia.

Acute leukemias are tumors in which early myeloid or lymphoid progenitors (blasts) accumulate in the bone marrow and to varying degrees spill into the peripheral blood and infiltrate other tissues. Leukemic blasts are so primitive as to be nonfunctional and tend to displace or suppress the production of normal hematopoietic elements in the marrow. As a result, most patients present with symptoms related to pancytopenia.


Acute leukemias and related disorders are aggressive neoplasms caused by acquired somatic mutations in early hematopoietic progenitors. The most obvious pathologic feature in the acute leukemias is the accumulation of undifferentiated blasts in the marrow and other tissues, indicating that, unlike the myeloproliferative neoplasms, acute leukemias have defects that block or significantly retard differentiation. We now know that specific subtypes of acute leukemia are often associated with mutations that alter the function of transcription factors that are required for normal differentiation of hematopoietic progenitors (Table 21-1). Sometimes these mutations consist of chromosomal rearrangements that create chimeric fusion genes, in which one or both partners encode a transcription factor; in other cases, the pathogenic mutations are more subtle point mutations or deletions. In most instances, the net result of the mutations is to decrease the function of a transcription factor that is required for the differentiation of cells of one or another of the hematopoietic lineages. An exception are mutations in the NOTCH1 gene, which increase the transcriptional activity of the NOTCH1 protein.

TABLE 21-1Examples of Transcription Factor Aberrations Associated with Specific Subtypes of Acute Leukemia

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