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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 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 disorders, 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 is mutations in the NOTCH1 gene, which increase the transcriptional activity of the NOTCH1 protein.

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

The expression of NOTCH1 genes bearing gain-of-function mutations in mouse hematopoietic stem cells causes the rapid development of T-cell acute lymphoblastic leukemia/lymphoma (T-ALL), the disease that is specifically associated with NOTCH1 mutations in man, proving that these mutations are leukemogenic. However, similar experiments performed with other transcription factor genes bearing leukemia-associated mutations that decrease or interfere with a normal transcriptional activity usually fail to produce acute leukemia or do so only after very long periods of time. In fact, when expressed in hematopoietic stem cells, some mutated transcription factors cause bone marrow failure, suggesting that their primary effect is to block differentiation rather than to cause proliferation. Further evidence that transcription factor mutations are not ...

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