Acute myeloid leukemia: Cytogenetic abnormalities

INTRODUCTION — Acute myeloid leukemia (AML) is associated with characteristic recurrent acquired chromosomal abnormalities. Many reflect reciprocal chromosomal translocations, which generate a fusion gene that encodes a chimeric protein that contributes to the pathophysiology of AML. Other cytogenetic abnormalities involve partial or complete loss or gain of a chromosome. Cytogenetic findings are important for the diagnosis and classification of AML, and some are associated with distinctive clinicopathologic features, have prognostic significance, and/or influence the choice of therapy.

This topic will review cytogenetic abnormalities in AML and their association with particular clinicopathologic features.

Related topics include:

●Clinical presentation and diagnosis of AML. (See "Clinical manifestations, pathologic features, and diagnosis of acute myeloid leukemia".)

●Classification of AML subtypes. (See "Acute myeloid leukemia: Classification".)

●Prognosis of AML. (See "Acute myeloid leukemia: Risk factors and prognosis".)

●Molecular abnormalities in AML. (See "Acute myeloid leukemia: Molecular genetics".)

TERMINOLOGY — Cytogenetics refers to the analysis of chromosomes. Karyotype refers to the entire complement of chromosomes.

Cytogenetic techniques — The most common techniques for clinical cytogenetic analysis of AML are:

●Chromosomal banding – Chromosomal banding refers to analysis of the karyotype using a chromosomal banding technique, in which Giemsa stain is used to produce a pattern of alternating light and dark segments (so-called, G-banding) that is unique to each pair of chromosomes (picture 1). Chromosomal banding is able to detect changes that affect relatively large regions of chromosomes, such as translocations, deletions, and aneuploidy.

●Fluorescence in situ hybridization (FISH) – FISH uses fluorescently-labeled DNA sequences that hybridize to complementary sequences of specific chromosomes and are visualized by fluorescence microscopy (picture 2). FISH is a more sensitive technique than chromosomal banding, but it only detects findings that correspond to the chromosomal sequences of the probe.

Other techniques (eg, chromosomal microarrays) are used less often for clinical cytogenetic analysis in AML. Advantages and disadvantages of various cytogenetic techniques are discussed separately. (See "General aspects of cytogenetic analysis in hematologic malignancies" and "Tools for genetics and genomics: Cytogenetics and molecular genetics", section on 'Chromosomal analysis'.)

Chromosomal abnormalities — Terms that are used to describe cytogenetic abnormalities include:

●Translocation (t) – Chromosomal translocation (t) is the process by which genetic material is exchanged between at least two different chromosomes. Reciprocal translocation refers to an exchange in which there is no obvious overall loss of chromosomal material. Rearranged chromosomes are identified in part by which chromosome has retained its centromere (the so-called derivative [der] chromosome). Standard nomenclature is to include the translocation in one set of parentheses and the breakpoints in a second set of parentheses. As an example, t(8;21)(q22;q22.1) describes a balanced translocation between chromosomes 8 and 21 that generates the RUNX1::RUNX1T1 fusion gene.

●Deletion (del) – Chromosomal deletion (del) describes loss of chromosomal material. An interstitial deletion results from two breaks in a single chromosome, with the loss of intervening material. An example is del(5q), in which a variable portion (often the segment between bands q14 and q33) of the long arm of chromosome 5 is lost.

●Monosomy – Monosomy refers to loss of an entire chromosome (eg, monosomy 7 or -7).

●Inversion (inv) – Chromosomal inversion (inv) requires two breaks in the same chromosome with rotation of the intervening material. An example is inv(16)(p13.1q22), wherein the MYH11 and CBFB genes, previously on opposite ends of chromosome 16, are juxtaposed after the rearrangement.

PREVALENCE — Using standard banding techniques, 50 to 60 percent of patients with de novo AML have abnormal karyotypes [1,2]. However, the frequency of cytogenetic abnormalities increases when techniques for culturing leukemia cells and for obtaining prophase and prometaphase chromosomes are used; some laboratories have reported clonal abnormalities in up to 85 percent of patients.

In a study of 5876 adults <60 years of age with newly diagnosed AML, 31 percent of patients had a single abnormality on karyotype analysis, whereas 2, 3, 4, and ≥5 abnormalities were seen in 13, 5, 2, and 7 percent of cases, respectively [2]. The most common karyotypes in AML were:

●Normal (41 percent)

●t(15;17)(q24.1;q21.2) and variants (13 percent)

●Trisomy 8 (10 percent)

●t(8;21)(q22;q22.1) and variants (7 percent)

●11q23.3 rearrangements (6 percent)

●inv(16)(p13.1q22)/t(16;16)(p13.1;q22) (5 percent)

SIGNIFICANCE OF ABNORMALITIES — Cytogenetic abnormalities are associated with important aspects of the pathogenesis, diagnosis, classification, management, and prognosis of AML:

●Pathogenesis – Many cytogenetic abnormalities (and their corresponding genetic changes) contribute to the pathogenesis of AML. Typically, chromosomal abnormalities associated with AML are recurrent (ie, non-random), acquired (ie, not inherited), and characteristic (not associated with non-myeloid malignancies).

Most of these karyotypic abnormalities reflect one of the following mechanisms:

•Rearrangements – Most cytogenetic changes in AML reflect a balanced reciprocal chromosomal rearrangement, in which an exchange of genetic material creates a fusion gene; the resultant chimeric protein is required, but is not sufficient, to cause leukemia. In most cases, the rearrangement involves two distinct chromosomes, such as t(8;21) or t(15;17); others are caused by an inversion of a single chromosome, such as inv(16) or inv(3).

•Deletions – In some cases, karyotypic abnormalities reflect loss of a large amount of chromosomal material, such as del(5q) or del(7q). In such cases, the chromosomal deletion contributes to leukemogenesis through loss of one or more tumor suppressor genes or other critical regulators of growth, differentiation, or cell death.

●Diagnosis – Certain chromosomal rearrangements, such as t(8;21), inv(16)/t(16;16), or t(15;17) are sufficient to diagnose AML, independent of the blast count in bone marrow or blood. Details of the diagnosis of AML are presented separately. (See "Clinical manifestations, pathologic features, and diagnosis of acute myeloid leukemia", section on 'Diagnosis'.)

●Classification – Cytogenetic abnormalities, along with microscopy, immunophenotype, and molecular findings, are required for contemporary classification of AML.

Cytogenetic and molecular abnormalities are key components of the preferred classification systems for AML: the World Health Organization 5^th edition (WHO5) [3] and the International Consensus Classification of Myeloid Neoplasms and Acute Leukemias (ICC) [4]. Cytogenetic and molecular findings are also used in guidelines for management and diagnosis of AML by the European LeukemiaNet [5]. (See "Classification of hematopoietic neoplasms".)

●Therapeutic impact – Detection of certain cytogenetic findings is critical for choosing therapy, such as t(15;17), which is associated with acute promyelocytic leukemia, or t(9;22), which is associated with Philadelphia chromosome/BCR::ABL1 AML.

●Prognosis – Certain cytogenetic abnormalities are associated with prognosis in AML [4-6]. As examples:

•Favorable prognosis – AML with t(8;21) or inv(16)/t(16;16)

•Intermediate prognosis – AML with t(9;11); KMT2A::MLLT3

•Adverse prognosis – AML with t(6;9); DEK::NUP214; AML with inv(3) or t(3;3); GATA2, MECOM; AML with t(9;22); BCR::ABL1; AML with del(5q), -7/del(7q), abnormal 17p, or complex karyotype

Some cases of AML do not display karyotypic abnormalities; instead, they are associated with chromosomal alterations below the threshold for detection by conventional cytogenetic techniques (ie, so-called submicroscopic abnormalities) and/or gene mutations. These findings are detectable by next-generation sequencing (NGS) panels or other molecular techniques. Mutations that contribute to the pathogenesis of AML are discussed separately. (See "Acute myeloid leukemia: Molecular genetics" and "Acute myeloid leukemia: Pathogenesis".)

RECURRENT TRANSLOCATIONS — Recurrent chromosomal abnormalities and their associated molecular findings are important for the diagnosis, classification, and/or prognosis in AML. (See "Clinical manifestations, pathologic features, and diagnosis of acute myeloid leukemia".)

t(8;21); RUNX1::RUNX1T1 — The reciprocal translocation t(8;21)(q22;q22.1) generates the RUNX1::RUNX1T1 fusion gene (previously AML1::ETO) (picture 1 and picture 2). The prognostic implications of t(8;21) differ between adults and children.

The presence of t(8;21) establishes the diagnosis of AML, regardless of blast count [7]. (See "Clinical manifestations, pathologic features, and diagnosis of acute myeloid leukemia", section on 'Diagnosis'.)

●Clinical – Clinical and prognostic features of t(8;21) differ between adults and children:

•Adults – The t(8;21) is found in 1 to 7 percent of adults with newly diagnosed AML; the age at presentation (25 to 30 years) is younger than that for the overall group of adults with AML [2,7]. Patients may present with a myeloid sarcoma. AML with the t(8;21) has a favorable prognosis in adults. In a large retrospective study, t(8;21) was associated with 97 percent complete remission (CR) and 61 percent 10-year overall survival (OS); disease-free survival (DFS) exceeded two years in patients treated with intensive post-remission consolidation chemotherapy, with only rare later relapses [2].

•Children – This is the most frequent chromosomal abnormality in children with AML. In contrast with adults, children with t(8;21) have had poor outcomes, particularly when accompanied by additional cytogenetic abnormalities, such as del(9q), or gain of chromosome 4 [8].

●Microscopy – This AML subtype exhibits predominantly neutrophilic maturation. Myeloblasts are relatively large, with abundant basophilic cytoplasm that often displays azurophilic granules [1,7,9]. Auer rods are easily identified; they may be present as a single long, sharp rod or as multiple distinct rods in a single cell. Eosinophil precursors are often increased in the bone marrow, but they do not exhibit cytologic abnormalities (as is characteristic of AML with inv(16)/t(16;16)).

●Cytogenetic findings – The t(8;21) is commonly associated with loss of a sex chromosome (-X or -Y) or del(9q). In rare cases, the malignant cells appear cytogenetically normal or exhibit only detectable -Y or del(9q), but fluorescence in situ hybridization (FISH) or reverse transcription polymerase chain reaction (RT-PCR) can demonstrate a cryptic RUNX1::RUNX1T1 fusion. (See "General aspects of cytogenetic analysis in hematologic malignancies".)

●Pathogenesis – The t(8;21) juxtaposes RUNX1 (previously AML1 or core binding factor alpha-2) on chromosome 21 with RUNX1T1 (previously ETO or MTG8) on chromosome 8 to form a RUNX1::RUNX1T1 fusion gene [10]. Normal RUNX1 is a component of the heterodimeric transcription factor, RUNX1::CBFB (formerly known as PEBP2 beta). RUNX1::CBFB binds and regulates genes that are critical to hematopoietic stem and progenitor cell growth and differentiation (eg, IL3, GM-CSF) and survival (eg, components of the JAK/STAT signaling pathway) [11,12]. The chimeric RUNX1::RUNX1T1 protein may both alter transcriptional regulation of normal RUNX1/CBFB target genes and activate new target genes. (See "Acute myeloid leukemia: Pathogenesis", section on 'Two-hit hypothesis of leukemogenesis'.)

Of note, the CBFB gene is located at 16q22, which is the breakpoint in the inv(16) and t(16;16) rearrangements. (See 'inv(16) or t(16;16); CBFB::MYH11' below.)

inv(16) or t(16;16); CBFB::MYH11 — AML with abnormalities of chromosome 16 are distinctive because, in addition to myeloblasts with monocytic and granulocytic features, they characteristically have abnormal eosinophils in the bone marrow or blood. The prognosis of these categories of AML is generally favorable.

The presence of inv(16)(p13.1q22) or t(16;16)(p13.1;q22) establishes the diagnosis of AML, regardless of blast count [7]. (See "Classification of hematopoietic neoplasms", section on 'Acute myeloid leukemia'.)

●Clinical – Abnormalities of chromosome 16 are seen in 5 to 7 percent of adults with newly diagnosed AML [2,7]. These leukemias typically have abnormal eosinophils in the blood and bone marrow and may present with a myeloid sarcoma. Patients with inv(16) or t(16;16) have a good response to intensive chemotherapy [2]. As an example, in one large study, patients with inv(16) or t(16;16) had high rates of CR (92 percent) and 10-year OS (55 percent) [2]. However, rare patients who have other abnormalities of chromosome 16 do not have a favorable prognosis.

●Microscopy – In AML with abnormalities of chromosome 16, the bone marrow typically reveals eosinophilia (>5 percent). There is no significant arrest of eosinophilic maturation, but the aberrant cells may exhibit large eosinophilic granules that can obscure the cell morphology. Naphthol AS-D chloroacetate esterase (CAE) staining is positive, in contrast with negative staining with normal eosinophils and in eosinophils associated with t(8;21). Myeloblasts may exhibit Auer rods.

●Cytogenetic findings – Abnormalities of chromosome 16 can be broadly divided into two groups:

•AML with the inv(16)(p13.1q22); CBFB::MYH11 (previously acute myelomonocytic leukemia or FAB M4Eo) (picture 3 and picture 4) accounts for most cases.

•AML with t(16;16)(p13.1;q22) is less common.

●Pathobiology – The inversion breakpoint at 16q22 occurs near the end of the coding region of the core binding factor beta (CBFB) gene, which encodes one subunit of the heterodimeric RUNX1::CBFB transcription factor. A smooth muscle myosin heavy chain gene (MYH11) is interrupted by the breakpoint on 16p. A fusion protein is produced containing the 5' portion of CBFB (which encodes the amino terminus, including the domain that heterodimerizes with RUNX1), fused to the 3' portion of MYH11. This portion of MYH11 contains a repeated alpha helical structure involved in myosin filament interactions and may be important in dimerization of the fusion protein in leukemia cells. The CBFB::MYH11 fusion protein appears to disrupt function of the RUNX1/CBFB transcription factor, repressing transcription of target genes that are critical to myeloid cell growth, differentiation, and function, as described above.

t(15;17); PML::RARA — Acute promyelocytic leukemia (APL) is a unique clinicopathological entity that is characterized by the presence of abnormal promyelocytes and life-threatening coagulopathy. It was called AML-M3 in the FAB classification. Nearly all cases of APL are associated with the t(15;17) and a chimeric transcription factor, PML::RARA, which is highly responsive to treatment with all-trans retinoic acid (ATRA) and arsenic trioxide (ATO).

The presence of t(15;17) establishes the diagnosis of APL, regardless of blast count [7]. (See "Classification of hematopoietic neoplasms", section on 'Acute myeloid leukemia'.)

●Clinical – APL represents a medical emergency with a high rate of early mortality, often due to hemorrhage associated with disseminated intravascular coagulation (DIC) and increased fibrinolysis [13]. Treatment with ATRA should begin as soon as the diagnosis is suspected by cytologic criteria and before definitive cytogenetic confirmation of the diagnosis; the diagnosis can usually be confirmed within 24 hours by FISH or polymerase chain reaction (PCR) for PML::RARA. The leukemic cells of APL are exquisitely sensitive to the differentiating effect of ATRA and patients have an excellent prognosis when ATRA is begun promptly. Diagnosis and management of APL are discussed separately. (See "Clinical manifestations, pathologic features, and diagnosis of acute promyelocytic leukemia in adults" and "Initial treatment of acute promyelocytic leukemia in adults".)

In typical cases of APL, the leukemic promyelocytes are hypergranular, but a minority of cases are the microgranular variant, which can be associated with extreme leukocytosis [7].

●Microscopy – The abnormal promyelocytes of hypergranular APL have characteristic folded, reniform (kidney-shaped) or bilobed nuclei, with coarse azurophilic granules and multiple Auer rods (picture 5) [7]. In the microgranular variant, the cytoplasmic granules are smaller or inapparent with a light microscope.

●Cytogenetic findings – The t(15;17)(q24.1;q21.2) rearrangement is seen in 13 percent of newly diagnosed AML and is highly specific for APL [2]. Rare APL variants include fusion of RARA at 17q21.2 with IRF2BP2 at 1q42.3, NPM1 at 5q35.1, ZBTB16 at 11q23.2, and STAT5B and STAT3 at 17q21.2 [14-16]. When the PML::RARA fusion is not detected by PCR or FISH in a patient with suspected APL, use of an RARA break-apart FISH probe can detect these rare variant translocations. Importantly, cases of APL that lack the t(15;17) do not respond to ATRA [15].

●Pathobiology – The breakpoint on chromosome 17 occurs within the first intron of the retinoic acid receptor gene alpha (RARA), which is fused to a breakpoint on chromosome 15 within the PML gene [15]. The translocation results in a PML::RARA fusion gene, which contains most of PML together with the DNA-binding and ligand-binding domains of RARA. The PML::RARA fusion protein is tightly associated with N-CoR (a ubiquitous nuclear protein that mediates transcriptional repression), and this can lead to persistent transcriptional repression that prevents differentiation of promyelocytes [15]. This effect can be overcome by ATRA, thereby relieving transcriptional repression and activating genes involved with terminal differentiation of promyelocytes. (See "Molecular biology of acute promyelocytic leukemia" and "Clinical manifestations, pathologic features, and diagnosis of acute promyelocytic leukemia in adults".)

t(9;11); KMT2A::MLLT3 — AML with t(9;11) is usually associated with monocytic or myelomonocytic features. This was previously called acute monoblastic leukemia (AMoL, AML-M5) in the FAB classification [17].

●Clinical – The t(9;11)(p21.3; q23.3) is more common in children than in adults [2,18]. It is present in 9 to 12 percent of pediatric AML, accounting for about three-quarters of the karyotypic abnormalities in infant AML. The t(9;11) accounts for 1 to 2 percent of adult AML cases and patients may present with DIC, myeloid sarcoma, or infiltration of the gingiva or skin.

AML with t(9;11) is generally associated with an intermediate prognosis. In one large study, patients with the t(9;11)(p21.3;q23.3) had 84 percent CR and 39 percent 10-year OS [2]. However, cases of t(9;11) that overexpress MECOM (discussed below) are associated with adverse prognosis [19].

●Microscopy – Monoblasts and promonocytes predominate and are usually strongly positive for nonspecific esterase but negative for myeloperoxidase.

●Cytogenetic findings – Rearrangements involving 11q23.3 are most often translocated to 9p21.3. However, fusion of 11q23.3 has been reported with 79 distinct translocation partner genes [20]. Secondary cytogenetic abnormalities are common, with gain of chromosome 8 seen most frequently. In addition to AML, rearrangements of 11q23.3 are also associated with acute lymphoblastic leukemia.

●Pathobiology – Translocations of 11q23.3 involve the KMT2A gene (previously called mixed-lineage leukemia; MLL), a histone methyltransferase that assembles large protein complexes that regulates gene transcription via chromatin remodeling [17]. The t(9;11) fuses KMT2A with MLLT3 (AF9). The AT hook DNA-binding motif and repression domain of KMT2A are retained in the fusion protein, but the strong activation domain is lost, leading to the absence of histone methyltransferase activity. Overexpression of MECOM (previously called EVI1) is present in >40 percent of cases of t(9;11); these cases generally have an adverse prognosis [19].

t(6;9); DEK::NUP214 — AML with t(6;9) may be associated with basophilia, pancytopenia, and dysplasia.

●Clinical – The t(6;9) may present with pancytopenia; the median white blood cell count is lower than in other types of AML. The t(6;9) is found in <2 percent of cases of AML; the median age of presentation is 35 to 44 years in adults and 13 years in childhood [2,18,21]. The prognosis is generally poor for both adults and children with AML with t(6;9); in one large study, rates of CR and 10-year OS were 88 and 27 percent, respectively [2].

●Microscopy – There are no specific features of the myeloblasts in this disorder, but ≥2 percent basophils in blood or bone marrow are present in approximately half of cases. Most cases exhibit granulocytic and erythroid dysplasia and ring sideroblasts may be seen.

●Cytogenetic findings – The t(6;9) is the sole cytogenetic abnormality in most cases, but it is occasionally associated with a complex karyotype.

●Pathobiology – The t(6;9) fuses DEK on chromosome 6 with NUP214 (also called CAN) on chromosome 9. This creates a nucleoporin fusion protein that acts as an aberrant transcription factor and also alters nuclear transport [22].

inv(3); GATA2, MECOM — AML with inv(3) or t(3;3) is associated with elevated platelet counts, dysplastic megakaryocytes, and multilineage dysplasia.

●Clinical – The inv(3) and t(3;3) account for approximately 1 to 4 percent of AML cases [2,23]. This abnormality is seen in de novo AML and in therapy-related myeloid neoplasms (t-MN). Patients typically present with anemia and a normal platelet count, but up to one-quarter of cases have marked thrombocythemia. Some patients manifest hepatosplenomegaly, but lymphadenopathy is uncommon.

This is an aggressive type of AML with short survival [23,24]. In 94 patients with AML with inv(3q)/t(3;3), monosomy 7 was the most common additional aberration, and it contributed to the adverse prognostic impact; rates of CR, five-year OS, and five-year relapse-free survival (RFS) were 31, 6, and 4 percent, respectively.

●Microscopy – Peripheral blood may reveal hypogranular neutrophils with a pseudo-Pelger Huët anomaly and there may be red blood cell abnormalities (eg, teardrop forms). Giant and hypogranular platelets are common and bare megakaryocyte nuclei may be seen. Bone marrow blasts have variable morphologic features, including myelomonocytic, megakaryoblastic, and undifferentiated blasts. Megakaryocytes may be normal or increased in number with small, bilobed, or non-lobated nuclei. Dysplasia of erythroid and neutrophil lineages is common and there may be an increase in marrow eosinophils, basophils, and/or mast cells. Fibrosis and bone marrow cellularity are variable; some cases present as hypocellular AML.

●Cytogenetic findings – Various abnormalities may involve 3q, with the most common being inv(3)(q21.3q26.2) and t(3;3)(q21.3;q26.2). Secondary karyotypic abnormalities are common, the most common of which are monosomy 7, del(5q), and complex karyotypes.

●Pathobiology – The inv(3) and t(3;3) involve MECOM (also called EVI1), which is repositioned near a distal GATA2 enhancer that activates MECOM expression and simultaneously confers GATA2 haploinsufficiency [25,26]. The chromosomal rearrangements are 5' of the gene in the t(3;3) and 3' of the gene in the inv(3). MECOM encodes a zinc-finger transcription factor that interacts with transcriptional and epigenetic regulators and mediates chromatin modifications and DNA hypermethylation. Depending on its binding partners, MECOM can act as a transcriptional activator to promote the proliferation of hematopoietic stem cells (eg, in a complex with GATA2) or as a transcriptional repressor inhibiting erythroid differentiation (eg, when bound to GATA1).

The t(3;21)(q26.2;q22.1) has been linked to t-MNs and aberrant expression of MECOM is often seen with the t(9;11). (See 'Therapy-related myeloid neoplasms' below and 't(9;11); KMT2A::MLLT3' above.)

t(9;22); BCR::ABL1 — AML with BCR::ABL1 is a newly-defined subtype of AML with defining genetic abnormalities in the WHO5 and ICC classification schemes [3,4]. These patients show no evidence of chronic myeloid leukemia (CML), and cases that meet the criteria for mixed phenotype acute leukemia, therapy-related myeloid neoplasms, or other AML types with recurrent genetic abnormalities are excluded from this category.

●Clinical – Patients usually present with leukocytosis with a blast predominance and variable levels of anemia and thrombocytopenia. Compared with patients who have myeloid blast transformation of CML, these patients are less likely to have splenomegaly and usually have lower degrees of basophilia (usually <2 percent) [27,28]. AML with BCR-ABL1 is an aggressive disease that responds poorly to a BCR::ABL1 tyrosine kinase inhibitor (TKI) alone or intensive AML induction therapy [28].

●Microscopy – The morphologic features of AML with BCR::ABL1 are nonspecific. Bone marrow cellularity is typically less than that seen with blast transformation of CML.

●Cytogenetic findings – All cases demonstrate t(9;22)(q34.1;q11.2) or molecular evidence of BCR::ABL1 (usually the p210 fusion). In most cases, other cytogenetic abnormalities, such as loss of chromosome 7, gain of chromosome 8, or complex karyotypes are also present [27,28].

●Pathobiology – BCR::ABL1 acts through multiple mechanisms, including changes in proliferation, aberrant maturation, and escape from apoptosis, as discussed separately. (See "Cellular and molecular biology of chronic myeloid leukemia".)

CHROMOSOMAL GAIN AND LOSS, COMPLEX KARYOTYPE, AND CLONAL HETEROGENEITY

Types of abnormalities — Gain or loss of specific chromosomes and/or complex karyotypes are commonly seen in AML. In some patients, there is evidence of chromothripsis, a genomic catastrophe that creates multiple gains and losses of chromosome regions and structural abnormalities.

●Gain or loss of chromosomes – Chromosomal gains and losses are seen in most types of AML, but certain abnormalities are more common with specific disorders. Any chromosome can be affected, but some chromosomes are more likely to be affected by a gain or loss. In a study of 354 patients with AML, the most common abnormalities were a gain of chromosome 8 (trisomy 8, 13 percent), and loss of chromosome 7 (9 percent); gain of chromosome 7 was rarely seen. Abnormalities of chromosome 7 are particularly characteristic of therapy-related AML associated with alkylating agents and/or radiation therapy [1]. Cases of AML with putative monosomy 5 appear to have retained chromosome 5 material (primarily from 5p) that has undergone submicroscopic rearrangement [29].

Cytogenetic analysis of pretreatment bone marrow specimens often reveals clonal heterogeneity with clonal evolution (ie, multiple, related subclones, particularly in patients with a complex karyotype). Clonal heterogeneity bears prognostic significance as an independent adverse prognostic marker in cytogenetically adverse-risk AML. In one study of 1274 patients with AML and abnormal clones, 33 percent showed clonal heterogeneity; among these, 60 percent had multiple subclones [30].

●Complex karyotypes – Complex karyotypes (≥3 numerical or structural chromosomal abnormalities) are frequently observed in AML with multilineage dysplasia or AML evolving from myelodysplastic syndromes/neoplasms (MDS) or myeloproliferative neoplasms (MPN), particularly in older patients. Deletion of chromosome 5, loss or deletion of chromosome 7, and loss of a whole chromosome 17 or 17p has a stronger negative impact on prognosis than other patterns of complex karyotypes in AML.

Approximately two-thirds of cases of AML with a complex karyotype include TP53 deletion or mutation and a high degree of genomic complexity (an average of 14 aberrations per case) [31]. TP53 mutations are closely associated with del(5q) (80 percent of del(5q) cases have TP53 mutations) [32]. Other findings include loss or deletion of chromosomes 7, 16, and 18; and gain of chromosomes 1 and 11. TP53 mutations can be part of an unbalanced chromosomal translocation, usually involving chromosome 5, resulting in a dicentric chromosome: dic(5;17). In one study of 136 cases of AML with complex karyotypes, 96 had deletion or loss of chromosomes 5, 7, and 17 with co-occurrence of TP53 mutation [33]. Conversely, patients without abnormalities of chromosomes 5, 7, or 17 were less likely to have TP53 mutations and more likely to have mutations of PHF6, FLT3, MED12, and NPM1; higher complete remission rate; and better overall survival. TP53 alterations are associated with a dismal outcome and are the most important prognostic factor in AML with a complex karyotype. Indeed, abnormalities of 17p or TP53 are associated with a high risk of treatment failure in AML, even after allogeneic hematopoietic cell transplantation [14,34]. AML with mutated TP53 (VAF ≥ 10%) defines a subtype of AML, according to ICC and ELN2022 [4,5].

●Chromothripsis – Chromothripsis refers to a "single event" genomic catastrophe that creates multiple gains and losses of chromosome regions and structural abnormalities (eg, marker, derivative, or ring chromosomes). Chromothripsis, which results from chromosome shattering, followed by random rejoining and repair of the resultant fragments, is associated with a poor prognosis. In one study, chromothripsis was identified in 6.6 percent of 395 adult patients with complex karyotypes [35]. Patients harboring chromothripsis frequently had TP53 loss or mutation, del(5q), high levels of copy number alterations (CNA), complex karyotypes, and alterations in DNA repair and cell cycle control genes. In another study, 36 percent of 49 marker or ring chromosomes showed features of chromothripsis with complex karyotypes, TP53 mutations, and dismal prognosis [36].

Specific findings — Deletion of the long arms of chromosomes 5 and 7 are among the most common in AML. Roles of genes that may contribute to leukemogenesis in these conditions are discussed separately. (See "Acute myeloid leukemia: Molecular genetics".)

del(5q) — Cytogenetic and molecular analysis of MDS and AML with del(5q) has identified a region of approximately 1 Mb in 5q31.1 that is deleted in all patients (referred to as the commonly deleted segment) and proposed to contain critical genes. A second commonly deleted segment has been identified in 5q32-q33.1 in patients with MDS with an isolated del(5q) (5q- syndrome). Genes located on 5q, including RPS14, miR-145/46a, TIFAB, CSNK1A1, EGR1, and APC have been implicated as haploinsufficient tumor suppressor genes in the development of myeloid disorders due to a gene dosage effect [37,38]. (See "Cytogenetics, molecular genetics, and pathophysiology of myelodysplastic syndromes/neoplasms (MDS)", section on 'del(5q)'.)

del(7q) — Distinct deleted segments of chromosome 7 have been associated with AML. A study of 81 patients with MDS or AML reported proximal breakpoints in q11.2-22 and distal breakpoints in q22-36. The smallest overlapping deleted segment was within q22 [37]. CUX1 (which acts as a haploinsufficient tumor suppressor) [39,40], SAMD9 (an endosome fusion facilitator) [41], EZH2 (an epigenetic regulator) [42,43], and other genes may be involved in leukemogenesis associated with del(7q). (See "Cytogenetics, molecular genetics, and pathophysiology of myelodysplastic syndromes/neoplasms (MDS)", section on 'Monosomy 7 and del(7q)'.)

AML WITH NORMAL KARYOTYPE — Using conventional cytogenetic techniques, AML with a normal karyotype accounts for nearly half of cases of de novo AML and up to 10 percent of therapy-related AML [44]. A normal karyotype can be seen in AML with various morphological features, and may be present in patients of variable age and clinical course [2,32]. In a study of 5876 young adults with newly diagnosed de novo or secondary AML, a normal karyotype was present in 41 percent; rates of complete remission and 10-year survival were 90 percent and 38 percent, respectively [2].

Next-generation sequencing (NGS) has identified mutations in many genes whose encoded proteins are involved in transcription (eg, RUNX1, CEBPA), signaling (eg, RAS, KIT, CBL, and FLT3), DNA methylation (eg, DNMT3A, TET2, IDH1/2, SETBP1), chromatin modification (eg, ASXL1, EZH2, KDM6A, KMT2A/MLL), and tumor suppressors (eg, TP53, WT1, PHF6). Some of these findings (eg, mutation of NPM1, CEBPA, TP53) had prognostic value, as discussed separately. (See "Acute myeloid leukemia: Risk factors and prognosis".)

THERAPY-RELATED MYELOID NEOPLASMS — Therapy-related myeloid neoplasms (t-MNs) refers to myeloid malignancies that are diagnosed in patients who were previously treated with DNA damaging agents (cytotoxic chemotherapy or radiation therapy). They comprise a continuum of diseases that includes therapy-related acute myeloid leukemia (t-AML), therapy-related myelodysplastic syndromes (t-MDS), and therapy-related MDS/myeloproliferative neoplasms (t-MDS/MPN) [9,37]. Cytogenetic abnormalities are found in >90 percent of cases of t-MN.

In the International Consensus Classification of Myeloid Neoplasms and Acute Leukemias (ICC) [4], these disorders are identified by describing the specific MDS, AML, or MDS/AML diagnosis, followed by the qualifier "therapy-related" (eg, AML with myelodysplasia-related cytogenetic abnormalities, therapy-related). In the 5^th edition of the World Health Organization (WHO5) classification, they are described as Myeloid neoplasms post cytotoxic therapy and diagnosis requires fulfilment of criteria for a myeloid neoplasm in addition to a documented history of chemotherapy or radiation therapy for an unrelated neoplasm. (See "Therapy-related myeloid neoplasms: Epidemiology, causes, evaluation, and diagnosis", section on 'Causes'.)

●Alkylating agents and ionizing radiation – Prior treatment with an alkylating agent (eg, cyclophosphamide, melphalan, cisplatin) or ionizing radiation is the most common cause of a t-MN and are associated with:

•Unbalanced aberrations – Many cases of t-MN are associated with unbalanced aberrations (primarily loss of chromosome material). Involvement of chromosomes 5 and/or 7 are characteristic of this subtype of therapy-related disease, representing 60 to 70 percent of cases.

•Translocations – Some specific translocations occur rarely in t-MN following multiagent chemotherapy. As an example, the NUP98 gene, which encodes a component of the nucleoporin complex, is located at 11p15.4; this site is the breakpoint for three distinct chromosomal rearrangements.

•Mutations – Mutations and loss of heterozygosity of TP53, located on chromosome band 17p13.1, are seen in up to half of cases of t-MN [45]. Mutations of TP53 are associated with abnormalities of chromosome 5 and a complex karyotype.

●Topoisomerase II inhibitors – DNA topoisomerase II inhibitors (eg, etoposide, teniposide, anthracyclines) are associated with a distinct subtype of t-MN. Balanced translocations associated with topoisomerase II inhibitors most often involve KMT2A (at 11q23.3) or RUNX1 (at 21q22.1) [37]. Topoisomerase II inhibitor therapy has also been associated with acute promyelocytic leukemia with t(15;17)(q24.1;q21.2) and acute lymphoblastic leukemia/lymphoblastic lymphoma with t(4;11) [46].

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient education" and the keyword(s) of interest.)

●Beyond the Basics topics (see "Patient education: Acute myeloid leukemia (AML) treatment in adults (Beyond the Basics)")

SUMMARY

●Description – Acute myeloid leukemia (AML) is associated with characteristic chromosomal abnormalities. Many of these abnormalities reflect reciprocal chromosomal translocations that generate a fusion gene, whereas others involve gain or loss of portions of chromosomes or entire chromosomes.

●Prevalence – More than half of cases of de novo AML have an abnormal karyotype when using standard banding techniques. The frequency of specific findings is presented above. (See 'Prevalence' above.)

●Significance – Cytogenetic abnormalities associated with AML are generally recurrent (ie, non-random), acquired (ie, not inherited), and characteristic (not associated with non-myeloid malignancies). (See 'Significance of abnormalities' above.)

•Diagnosis and classification – Cytogenetic analysis is an essential aspect of diagnosis and classification of AML according to contemporary classification schemes: the World Health Organization 5th edition (WHO5) system and the International Consensus Classification of Myeloid Neoplasms and Acute Leukemias (ICC). Certain chromosomal rearrangements, such as t(8;21), t(16;16), or t(15;17) are sufficient to diagnose AML, independent of the blast count in bone marrow or blood.

•Treatment, prognosis, and pathophysiology – Cytogenetic and molecular findings are also important for selection of therapy, prognosis, and understanding the pathobiology of AML.

●Recurrent translocations – Reciprocal translocations that generate fusion proteins are commonly associated with specific categories of AML. The clinical, prognostic, pathologic, cytogenetic, and molecular features of the most common recurrent translocations are described above. (See 'Recurrent translocations' above.)

●Chromosomal gain or loss – Gain or loss of specific chromosomes and/or complex karyotypes (ie, ≥3 numerical or structural chromosomal abnormalities) are common. Chromosomal gains and losses are seen in most subtypes of AML. Any chromosome can be affected, but some chromosomes are more likely to be affected by a gain (eg, chromosome 8) or loss (eg, chromosome 7). (See 'Chromosomal gain and loss, complex karyotype, and clonal heterogeneity' above.)

●Therapy-related myeloid neoplasms (t-MNs) – t-MNs are myeloid malignancies that arise after treatment with cytotoxic chemotherapy and/or radiation therapy. Particular types of cytogenetic abnormalities are associated with specific therapies. (See 'Therapy-related myeloid neoplasms' above.)