Introduction

Acute myeloid leukemia (AML) is a complex and heterogeneous disease. However, major strides have been made in our understanding of the molecular pathogenesis of AML based on the cloning of more than 100 disease alleles. These insights in turn have generated strategies for improving treatment outcome and minimizing the toxicity of therapies. Although the genotypic diversity of AML might suggest that it would be challenging to develop molecular targeted therapies for each genotypic variant, there are common themes in the pathways of transformation. For example, many translocations and point mutations in myeloid leukemias target shared signal transduction pathways that confer proliferative and survival advantages on hematopoietic progenitors. Other mutations target hematopoietic transcription factors, and phenotypi-cally result in impaired hematopoietic differentiation. It may therefore be possible to develop therapeutic strategies that target these shared pathways of transformation.

There are considerable data showing that AML, like other human cancers, is the consequence of more than one mutation. These data include epidemiological and genotypic data demonstrating that many AMLs have more than one recurring mutation, as either point mutations or chromosomal translocations. In addition, emerging data from animal models of leukemia strongly support the multistep pathogenesis of disease. Rare inherited leukemia syndromes provide strong evidence in support of more than one mutation, as do childhood leukemias in which the expression of a leukemia oncogene can be detected at birth but the leukemia does not develop until later in life.

Analysis of the catalog of mutations that have been cloned in human acute leukemias has suggested that disease alleles can be broadly divided into two categories: those that confer a proliferative and/or survival advantage on hematopoietic progenitors and those that impair hematopoietic differentiation.

Mutations that confer a proliferative and/or survival advantage

Gain-of-function mutations in certain genes confer proliferative and/or survival advantages on hematopoietic progenitors, usually as a consequence of aberrantly activating signal transduction pathways. Examples in myeloid leukemias include activating mutations in RAS family members, in the receptor tyrosine kinases KIT and FLT3 (discussed in more detail below), loss of function of NF-1, and, more recently, gain-of-function mutations in the hematopoietic phosphatase SHP-2. It is of note that although these mutations collectively account for as many as 50% of cases of AML, with rare exceptions only one of these is mutant in any given patient. This epide-miological observation suggests that these mutations can be viewed as a complementation group, and that any one of these is sufficient to confer proliferative and survival advantages on a leukemic cell (Figure 4.1).

The most common of these is the hematopoietic receptor tyrosine kinase FLT3, which is constitutively activated by acquired mutation in approximately 30-35% of AMLs. In 20-25% of cases of AML, there are internal tandem duplications (ITDs) in the juxtamembrane domain of FLT3, ranging in size from several to more than 50 amino acids. In each case, the consequence of the ITDs is constitutive activation of FLT3 tyrosine kinase activity. Although the mechanism of FLT3 activation by ITD mutations is not fully understood, a working hypothesis is that the ITDs result in loss of function of negative autoregulatory modules in the juxtamembrane

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