AML with Complex Karyotype (Secondary Cytogenetic Aberrations)

AML without the balanced chromosomal rearrangements (eg, t(8;21), inv(16)/t(16;16), and t(15;17)), but with at least 3 acquired chromosomal aberrations is defined as complex karyotype AML. There may be a low frequency of NPM1, FLT3, CEBPA, RAS and KIT gene mutations. There is an occurrence of chromosomal imbalances, with chromosomal losses occurring more frequently than chromosomal gains, and regarded as the worst prognostic group (Table 3). Patients with monosomal karyotype (MSK) abnormalities show an inferior OS. Incidence of AML with complex karyotype is increasing with age and constitutes 10–12% of all AML. This kind of AML seems to be induced by the deregulation of molecular pathways involved in genome stability.6,7,9 For instance, two-thirds of complex karyotype AML are identified with TP53 mutations and loss of p53 function which resulting in genetic instability (Table 3). Another contributing mechanism is chromosomal deletions and inactivation of a single allele, eg, deletion of 5q32 (RPS14 gene) identified for the −5q myelodysplastic syndromes. Genomic gain or amplifications associated with oncogene activation is another mechanism common in this type of AML. This mechanism includes members of the ETS gene family: eg, ERG/ETS2 located on 21q, and ETS1/FLI1 mapped to band 11q23.3-q24.1 (Table 3).2,6

The rearrangements of Nucleoporin 98 (NUP98) occur in a wide range of hematopoietic malignancies which including both ALL and AML. NUP98 has several different partners comprising two groups: the HOX partner genes (HOXA9, HOXA11, HOXA13, HOXC11, HOXC13, HOXD11, HOXD13, PRRX1/PMX1, and PRRX2) and the non-HOX partner genes (FN1, RAP1GDS1, NSD1, WHSC1L1/NSD3, PSIP2/LEDGF, ADD3, DDX10, and TOP1). The rare but recurrent translocation t(7;11)(p15;p15.5) causes fusion of NUP98 gene to the HOXA9 gene. The fusion occurs at the gly-leu-phe-gly (GLFG)-repeated domains of NUP98. In inv(11)(p15.5;q31), the acidic domain of a putative helicase encoded by the DDX10 gene fuses to the NUP98-GLFG repeat domains. This inversion frequently occurs in therapy-related AML (t-AML). Moreover, 5q deletion associated with the recurrent t(5;11)(q35;p15.5), frequently occurs in pediatric AML and disrupt NUP98 at 11p15.5. In translocation t(5;11), the conserved finger domains SET, SAC, and PHD of the NSD1 gene can fuse to the NUP98-GLFG repeat domains. Clinically, the incidence of NUP98 rearrangements is quite low in childhood AML, which appear with an aggressive clinical course and unfavorable therapeutic outcomes.5,6,10

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ETS-related gene (ERG) at 21q22 is a cryptic amplification and frequently amplified in AML patients with a complex karyotype. ERG is a member of the ETS gene family (which has more than 30 members). Generally, the ETS gene family members are downstream nuclear targets of signal transduction pathways promoting cell proliferation and tissue invasion. Herein, recurrent amplification of ERG leads to its over-expression in complex karyotype AML, wherein contributing to an aggressive malignant phenotype. Additionally, ERG over-expression increases RR and short survival in AML with normal karyotype. High ERG expression in presence of MLL-PTD predicts a worse cumulative incidence of relapse (CIR).15

The incidence of AML with monosomy 7 and deletion of 7q [(del(7q)] is approximately 5% to 7%. AML patients exhibit del(7q) would experience an unfavorable outcome. Additionally, myelodysplastic syndrome (MDS), Fanconi anemia, congenital neutropenia, and neurofibromatosis are conditions characterized by del(7q) as a sole cytogenetic abnormality which are frequently followed by secondary AML. Individuals with these constitutional disorders are predisposed to myeloid leukemia. The balanced rearrangement of 7q22 or 7q32-q35 leads to the loss of chromosome 7 and AML. These regions contain the gene of a putative tumor suppressor that controls myeloid growth and regulates differentiation, whose loss of function leads to leukemic transformation. The deletion of a single allele leads to abnormal growth due to the reduced level of the tumor-suppressor protein, while inactivation of both alleles transformed immature myeloid cells to the leukemic phenotype.9,10

Generally, the incidence of chromosomal aberrations is higher in pediatric patients than in adults (approximately 76% of childhood AML, compared to 55% of adult AML) (Figure 4). For example, balanced rearrangements at 11q23 are on average four times more common in children than in adults. The frequency of 11q23 rearrangements in AML decreases appreciably with age. Likewise, the incidence of t(8;21) is twice as common in pediatric as in adult AML. In contrast, −5, del(5q) and other unbalanced structural abnormalities resulting in loss of material from 5q are much more frequent in adult than in childhood AML. Likewise, both inv(3)(q21q26)/t(3;3)(q21;q26), which are found in 2% of adults, are extremely rare in children and have so far never been detected in a patient with de novo AML younger than 12 years (Figure 4).8,16 The varying proportions of specific chromosomal aberrations existing between pediatric and adult AML can be attributed to the molecular reason and biological differences.

AML with Various Cytogenetic Abnormalities

Non-random chromosomal rearrangements with unbalanced translocations may result in monosomies (monosomy 7), deletions of part or all chromosome 5 or 7 (−5/−7 AML) and trisomies (eg 8, 11, 13 and 21 trisomies).9,10 The most common trisomies in de novo AML are, in decreasing order of frequency, +8, +22, +13, +21 and +11.15 Notably, in this cytogenetic subset of AML, gene mutations such as CEBPA and NPM1 are occurring, which acting as class II mutations in the collaboration with class I alterations occurred in the chromosomal abnormality.1,2

An enormous clinical heterogeneity is seen among patients whose leukemic cells exhibit trisomy 8 that can be associated with an intermediate or poor prognosis.1,2,19 The trisomy 8 is likely to be a primary event modulating underlying cryptic translocations, deletions, or mutations.19 This aberration represents a mechanism to achieve the amplification of oncogenes required for leukemogenesis. Trisomy 8 causes an increasing dosage of oncogenes, including c-myc (8q24), c-mos (8q22), and ETO (8q22), significance in leukemogenesis.1,19

Trisomy 11 is a rare event in AML associated with FAB-M1 morphologic features and shows an intermediate to poor prognosis. Trisomy 11 represents a class I aberration conferring proliferation and apparent cell survival advantages to the clone, whereas a class II mutation impairs cellular differentiation. Cases of MDS with +11 show a high risk of progression to AML. A quantitative increase in the production of oncogenes including Cyclin D1 gene (11q13, regulating cellular transition from G 1 to S phase), and MLL gene (11q23, over-expressed in both myeloid and lymphoid leukemic cells, and in an elevated proportion of mixed-lineage leukemia) is observed. MLL plays a key role in hematopoiesis by regulating HOX genes, which sequentially involved in hematopoietic stem-cell renewal and leukemogenesis.15,10 The well-known proto-oncogene WT1 expressed in various cell types to promoting proliferation is mapped to 11p13 band.2,8

This trisomy is a rare chromosomal abnormality cooperated with a high frequency of mutations in RUNX1 and spliceosome genes and characterized with poor prognosis. Trisomy 13 represents a class I alteration associated with the amplification of oncogenes and over-expression of FOX1 and FLT3 (13q12), a potential mechanism for leukemogenesis. The frequent morphology of AML+13 cells is associated with FAB M0 and showing a high frequency (80% to 100%) of RUNX1 mutations. As the master regulator of hematopoietic differentiation, AML1 (RUNX1) mutations function as a transcriptional repressor that blocks AML1-dependent HPC differentiation.2,20

The pathogenesis of MDS/AML associated with monosomy 7 is mediated by gene dosage effects as class I alterations, identified by microarray analysis. Monosomy 7 is one of the most frequent chromosomal abnormalities observed in patients with MDS/AML and associated with poor clinical outcome, both in MDS and in AML. This aberration represents a primary event superimposed to the Philadelphia chromosome in chronic myelocytic leukaemia (CML) and in a variety of Mendelian and non-Mendelian predisposing disorders wherein subjects developing MDS/AML. The methods to monitor the monosomic clone and the parental origin of the chromosome 7 loss are FISH and QR-PCR.5,10,21

Cytogenetically Normal (CN) AML with Gene Mutations

A large subset of AML (~40–50% of adult and 25% of pediatric AML) (Figure 4) is cytogenetically normal (CN-AML), but a number of gene mutations, as well as deregulated expression of genes, have been identified in this subset (Table 4). AML patients with a normal karyotype (CN-AML) are considered to be at intermediate risk associated with 5-year survival rates between 24% and 42%.3,8 In CN-AML, mutations in specific genes are identified: the nucleophosmin 1 (NPM1) gene, the fms-related tyrosine kinase 3 (FLT3) gene, the CCAAT/enhancer-binding protein alpha (CEBPA) gene, the myeloid-lymphoid or mixed-lineage leukemia (MLL) gene, the neuroblastoma RAS viral oncogene homolog (NRAS) gene, the Wilms tumor 1 (WT1) gene, and the runt-related transcription factor 1 (RUNX1) gene (Figure 3A). These gene mutations are the most prevalent in CN-AML; however, these also occur in AML with abnormal karyotypes as secondary abnormalities (Figure 2) (Tables 2 and 4).11,18

Interestingly, class I mutations in KIT are exclusively associated with inv(16) and t(8;21), being rare in other AML subtypes and are associated with unfavorable outcomes.1,2

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