To date, more than 80 recurring balanced chromosomal rearrangements associated with AML have been characterized at the molecular level (see Table 30-2). Such rearrangements typically lead to the formation of chimeric fusion proteins, which are believed to play a key role in mediating the leukemic phenotype. A clear pattern is emerging whereby chromosomal rearrangements disrupt genes encoding transcription factors that under normal circumstances are directly involved in the regulation of hematopoiesis (reviewed in References 2 and 3). Notable examples include disruption of genes encoding the het-
erodimeric core binding factor (CBF) complex, which is comprised of a and P subunits by the t(8;21)(q22;q22) and inv(16)(p13q22)/t(16;16)(p13;q22) rearrangements, respectively, which lead to formation of AML1(CBFa2/RUNX1)-ETO and CBFP-MYH11 fusions, respectively. A further example is provided by the involvement of RARa in fusion proteins resulting from rearrangements of 17q21 in acute promyelocytic leukemia (APL). Retention of dimerization, DNA-binding domains, or both within the resultant chimeric fusion proteins provides the potential to alter the pattern and repertoire of regulation of downstream target genes. A growing family of oncogenic fusion proteins, which include AML1-ETO and those involving TEL and RARa, have been shown to recruit nuclear corepressor complexes including histone deacetylase (HDAC), leading to tran-scriptional repression of genes implicated in normal hematopoietic differentiation.
Involvement of genes that encode proteins with a direct influence on chromatin remodeling or with transcriptional regulatory properties provides another recurring theme in the development of AML. Amongst this group are translocations involving the MLL gene at 11q23, as well as rearrangements disrupting genes encoding MOZ, TIF2, P300, and CBP. Deregulation of class I homeobox (HOX) genes, which encode transcription factors that play a key role in pattern formation and organogenesis during embryonic development, as well as contributing to the organization and regulation of hematopoiesis, provides a further common mechanism in the development of AML. A rarer target for AML-associated translocations involves genes encoding components of the nuclear pore complex, which plays a role in transport between nucleus and cytoplasm, for example, NUP98 and CAN (NUP214) disrupted by rearrangements of 11p15 and 9q34 (most commonly t(6;9)(p23;q34), leading to DEK-CAN fusion), respectively.
The generation of chimeric fusion proteins, through chromosomal translocations, which lead to a block in differentiation and contribute to the biological characteristics of different subsets of leukemia, is generally believed to be a primary event in the pathogenesis of AML. The
Table 30-1. Factors Predisposing to the Development of Secondary AML Genetic Predisposition
Down syndrome Fanconi anemia
Other inherited bone marrow failure syndrome: Shwachman-Diamond Diamond-Blackfan Dyskeratosis congenita Kostmann's
Familial platelet disorder DNA repair defects, e.g., Bloom's syndrome Other tumor predisposition syndromes, e.g., Li-Fraumeni
Prior Hematologic Disorder
Chronic myeloid leukemia Other myeloproliferative disorders Myelodysplastic syndrome Paroxysmal nocturnal hemoglobinuria
Chronic exposure to benzene and derivatives Ionizing radiation Chemotherapeutic agents Alkylating agents Topoisomerase II-targeting drugs functional properties of the majority of AML-associated fusion proteins are quite distinct from those generated by chromosomal translocations associated with myeloprolif-erative disorders, which typically involve genes encoding components of signal transduction pathways and lead to formation of chimeric proteins with aberrant kinase activity that provide bone marrow progenitors with a prolifer-ative advantage (see chapter 35). Such fusion proteins are rare in AML, with BCR-ABL occurring in only approximately 1% of cases. Nevertheless, over the last few years it has become apparent that mutations in genes encoding components of the signal transduction pathways are frequent in AML; these include activating mutations of FLT3, RAS, KIT, and SHP2. This latter class of mutations has been proposed to cooperate with the chimeric oncoproteins generated by AML-associated translocations, thereby endowing hematopoietic progenitors with the combined effects of a block in differentiation coupled with a proliferative advantage.2 These are critical events in the development of the AML phenotype.
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