Approximately 15% to 20% of patients with AML have a numerical gain or loss of a single chromosome as the sole primary karyotypic abnormality. Each of the autosomes and sex chromosomes can contribute to the numerical changes. The most common trisomies in decreasing order of frequency are gain of chromosome 8 (Figs1 and 2), 11, 13, 22, 21, 14, and 9 and most common monosomies include −5, −17, and −7. The gain of chromosome 8, the most frequent abnormality seen in AML, is a sole abnormality in 6.3% of cases and overall occurs in 16% of cases. The incidence of +8 detected by FISH varies between 19% and 25% of AML cases. The prognosis of AML with +8 depends on whether +8 occurs as an isolated abnormality or accompanies other cytogenetic aberrations. In the latter situation, +8 does not appear to adversely affect the favor able outcome of patients with t(15;17), inv(16)t(16;16), and t(8,21). By contrast, patients with +8 and a complex karyotype and/or an unfavorable aberration such as del(5q) or −7 usually have a very poor outcome. Isolated +8 has been considered to be associated with either intermediate or unfavorable prognosis.
Fig1. GAIN OF CHROMOSOME 8 DETECTED AT RELAPSE OF ACUTE MYELOID LEUKEMIA. All evaluated cells had a gain of chromo some 8. Four related cell populations evolved: (A) 35% of cells had +8, (B) 25% of cells had tetrasomy 8, (C) 35% of cells had a gain of an isochromosome of 8q and a deleted 17p and loss of TP53 (not shown). The i(8q) is a novel abnormality not previously observed in multiple testing from the diagnosis (a year earlier) but del (17p) was observed in 11% of cells at diagnosis, indicating genomic instability as a result of TP53 deletion. (D) Shows a metaphase cell after FISH with two homolog 8 and the presence of i(8q) (two red arrows). (E) Shows an interphase FISH with 4 red signals (MYC at 8q24) and 4 centromeres (green) indicating a cell with tetrasomy 8 detected in 58% of cells while 11% had 3 copies of #8 whereas 24% of cells had 4 copies of MYC and 3 copies of centromere 8 consistent with i(8q).
Fig2. STRUCTURALLY ABERRANT CHROMOSOMES 8 AND 11 IN A NEWLY DIAGNOSED PATIENT WITH ACUTE MYELOID LEUKEMIA. (A) 90% of cells had a loss of Y chromosome and a gain of an aberrant chromosome 8 in two copies. The derivative chromosome 8 first resulted from an unbalanced translocation between the long arms of chr(8) and chr(11) which entirely replicated itself leading to a gain of chr(8) and four copies of 11q. (B) A partial karyotype from another cell showing two copies of der(8)t(8;11). (C) Additionally, 10% of cells showed an alternative aberrant chromosome 8 present in one copy with a gain of an additional aberrant copy in the form of an isoderivative chr(8). Ider(8)t(8;11) was produced from an unbalanced translocation between 8q and 11q and a subsequent replication of the proximal region leading to two identical arms of the aberrant chromosome, resulting in four copies of 8q, and five copies of 11q. (D) Partial gains of 8q and 11q are rare recurrent abnormalities found in myeloid malignancies. According to the 2017 ELN recommendations, these results are associated with an intermediate-adverse risk category. (D) Array testing detected trisomy and tetrasomy of chromosome 8 (a ∼146.4 Mb gain 8p23.3q24.3) and partial gain of the long arm of chromosome 11q (∼35.2 Mb 11q22.1q25) (blue).
MYC Amplicon in Acute Myeloid Leukemia
In normal cells, MYC gene is localized on chromosome 8, band region q24.21. Less than 1% of hematologic malignancies have genomic amplification and they are usually associated with an elderly age and poor prognosis. Genomic amplifications are cytogenetically identified as homogeneous staining regions (HSR), DM, and ring chromosomes. Gene amplification(s) in hematologic malignancies is a rare entity (<1%). Using a comprehensive and high-resolution genomic method, analysis of 23 patients with MYC-amplification revealed amplicon heterogeneity in 65% of these patients and in 48% deletions of 8q24 segment was observed. Moreover, amplification of 8q24 region has been observed in a ring structure suggesting that 8q24 amplicon architecture is shared between different chromosomal structures. Discovery of neocentromere in these patients may represent scattered acentric DM as well as HSR resulting in mitotic stabilization, and providing an adaptive advantage of leukemia cells harboring 8q24 amplicon.
Deletion of 17p often results in the loss of tumor suppressor TP53 gene on band p13.1, which has been reported in 5% to 9% of adult AML patients. The abnormalities of 17p are often associated with other chromosomal aberrations such as del(5q), −5, −7, but is an independent poor-risk prognostic factor.
TP53 mutations are more common in older patients and those who have previously received alkylating agents. These patients have an increased number of CD34+ cells, suggesting that the loss of TP53 function could cause cell cycle arrest. Based on genomic classification of 1540 AML patients treated in different intensive chemotherapy trials, theTP53-mutation-positive subgroup of patients consisted of complex cytogenetic alterations or isolated chromosome losses or gains and were associated with an adverse prognosis. Therefore, it has been proposed that testing for deletion and mutation of TP53 should be included in the ELN and WHO classification system of AML (Figs. 3 and4).
Fig3. COMMON MUTATIONS IN DE NOVO AND SECONDARY ACUTE MYELOID LEUKEMIA. A number of clonal blood disorders with a myeloid phenotype are represented. Each of these disorders is characterized by recurrent mutations in specific genes, some of which are shared between several different phenotypes (e.g., TET2). All of these disorders can transform to secondary AML upon acquisition of additional somatic mutations. When AML arises in the absence of an antecedent clonal blood disorder, it is known as primary AML. aCML, Atypical CML; AML, acute myeloid leukemia; CML, chronic myeloid leukemia; ET, essential thrombocytopenia; IMF, idiopathic myelofibrosis; PV, polycythemia vera; SM, systemic mastocytosis. (Reprinted with permission from Grove CS, Vassiliou GS. Acute myeloid leukaemia: a paradigm for the clonal evolution of cancer? Dis Model Mech. 2014;7:941.)
Fig4. FUNCTIONAL OVERLAP OF ACUTE MYELOID LEUKEMIA DRIVER MUTATIONS. Driver mutations in AML stratified mechanistic consequences. Size of circles reflect mutational frequency with three most common mutations in larger type. (Reprinted with permission from Kihstagari A, Levine RL, Viny AD. Driver mutations in acute myeloid leukemia. Curr Opin. 2020;27:49.)
