A well-known procedure to distinguishing tumor genotypes and classify different subgroups of AML was proposed by the World Health Organization (WHO), through using morphologic, immunologic, cytogenetic and molecular biologic classification techniques (MICM). The classification scheme was proposed to distinguish different genetic and molecular abnormalities in the diagnosis of AML and provides a framework for clinical management. It especially emphasizes the importance of genetic test results to define clinically relevant disease entities in conjunction with morphology, immunophenotype, and other clinicopathologic features.7–8

However, for any samples suspected for AML, karyotyping is first required; if it is normal, then the fluorescent in situ hybridization (FISH) or reverse transcriptase-polymerase chain reaction (RT-PCR) technique is essential to detect cryptic rearrangement of the relevant locus (Table 1). This genetic approach seems to be used in clinics for initial diagnosis and decision made on therapeutic choices. Then, at the time of first remission or relapse, additional testing is ordered to refine prognosis.9–11

Table 1

Genetic Abnormalities in AML (a Collaboration of at Least Three Types of Mutations)


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Based on the cytogenetic and molecular analysis and according to the risk stratification, AML genetic aberrations are placed into three categories; 1) Non-random chromosomal aberrations including balanced translocations, inversions, deletions, monosomies, and trisomies (Tables 2 and 3), 2) Multiple gene mutations (Table 4) and 3) Epigenetic alterations (Table 5).6,12–14

Table 2

Table 3

Table 4

Table 5

Actually, aberrations should occur in genes relevant for pathogenesis, ie, master transcription factor fusions (18% of cases), NPM1 (27% of cases), tumor-suppressor genes (16%), DNA-methylation-related genes (44%), signaling genes (59%), chromatin-modifying genes (30%), myeloid-transcription genes (22%), cohesion complex genes (13%), and spliceosome complex genes (14%).1,3,7

At the molecular level, AML is the consequence of collaboration between at least three broad classes of gene alterations (Table 6 & Figure 1). Class I gene alterations are those aberrations that activating signal transduction pathways and enhancing proliferation with survival advantages of hematopoietic stem cells. This class of gene aberrations can involve and activate the receptor tyrosine kinase FLT3 and Kit or the RAS-associated signaling pathway. Class II gene alterations affect a master transcription factor or a protein involved in hematopoietic differentiation. This second aberration would impair differentiation of a hematopoietic progenitor cell (HPC) and aberrant acquisition of self-renewal properties whereby increase the likeliness of malignant transformation. Outstanding examples for this class of aberrations are the recurring gene fusions RUNX1-RUNX1T1 and PML-RARA resulting from t(8;21), inv(16)/t(16;16) and t(15;17) rearrangements, as well as mutations in CCAAT enhancer-binding protein A (CEBPA) and nucleophosmin 1 (NPM1) genes.15,16,17

Table 6

Figure 1

Class 0/III are those alterations that promote epigenetic modifications of chromatin in a large area and affect further transcription factors or components of the transcriptional co-activation complexes whereby would confer malignant transformation to the HPCs and lead to overt AML (eg, DNMT3A and IDH1/2, involved in epigenetic regulation of chromatin and cellular processes). Class 0/III alterations, however, can also be happened before class I.2,6,12,13

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