Acute myeloid leukemia (AML) results from the maturational arrest of bone marrow cells in the earliest stages of development. Although the mechanism of cell arrest is still under investigation, many individuals with AML have chromosomal translocations and other genetic abnormalities that activate or inactivate driver genes. The developmental arrest of immature blood cells results in two distinct disease processes. First, the rapid proliferation of abnormal myeloblasts, and their reduced ability to undergo apoptosis, results in their accumulation in the bone marrow, blood, spleen, and liver. Secondly, the accumulation of these immature myeloblasts prevents the production of normal blood cells, leading to varying degrees of anemia, thrombocytopenia, and neutropenia.

There are different forms of AML, usually divided into de novo AML and secondary AML. Secondary AML usually refers to AML that develops due to a therapy-related issue or is AML with myelodysplasia-related changes that either has transformed from a pre-existing bone marrow disorder, such as myelodysplastic syndrome (MDS), myeloproliferative neoplasm, or has very significant amounts of signs of myelodysplasia or cytogenetic changes associated with myelodysplasia (AML-MRC). Typically, secondary AML is more difficult to treat, is more common in older patients, and is sometimes more resistant to standard chemotherapy.1 Prior exposure to chemotherapy and/or radiation is an important risk factor for AML, particularly as medical advances increase the number of patients who survive a previous malignancy. Approximately 10% to 30% of all cases of AML arise after exposure to chemotherapy or radiation for a prior malignancy or autoimmune disease.1,2 Patients with therapy-related, or secondary, AML (tAML, sAML) are more likely to have adverse cytogenetics than patients with de novo AML. In particular, 11q23 translocations and complex and monosomal karyotypes are overrepresented in tAML patients. This is likely the result of mutational events induced by chemotherapy in surviving hematopoietic progenitor cells. Patients with previous exposure to chemotherapeutic agents can be divided into 2 subgroups: those with previous exposure to alkylating agents and those with exposure to topoisomerase-II inhibitors. Acute leukemia typically develops 5-10 years after the use of alkylating agents and 1-5 years after the use of topoisomerase inhibitors. Patients with prior exposure to alkylating agents often have a myelodysplastic phase that precedes the development of AML, and cytogenetic testing has identified 5q- or monosomy 7 as frequent chromosomal abnormalities in these patients. In patients with topoisomerase inhibitor exposure, cytogenetic testing reveals frequent 11q23, inversion 16, or t(15;17) translocations.1,3 Overall, patients with therapy-related AML have shorter overall survival and poorer outcomes than de novo AML cases.

Relapse and treatment refractoriness in AML are caused by a small number of quiescent leukemia stem cells (LSCs) that are resistant to conventional chemotherapy. Targeting resistant LSCs may help lead to a cure for AML without the need for hematopoietic stem cell transplants (HSCTs). Recent research has identified high levels of BCL-2 overexpression as a defining characteristic of LSCs.4 The mitochondrial-mediated pathway of apoptosis is regulated by the balance of the BCL-2 family of antiapoptotic (BCL-2, BCL-X, MCL-1) and proapoptotic proteins (BAX, BAD, and BAK). BCL-2 inhibits apoptosis by inactivating BAX and BAK.5 Increased expression of pro-survival BCL-2 relative to the pro-apoptotic protein BAX is associated with reduced complete remission rates, earlier relapse, and inferior overall survival in patients receiving intensive chemotherapy for AML. Inhibition of BCL-2 targets mitochondrial energy metabolism and selectively induces apoptosis in LSCs.4 Because impaired apoptosis plays a key role in cancer resistance to therapy, pharmacologic inhibition of anti-apoptotic proteins, especially BCL-2, represents an attractive way to destroy clonal cells.6


Genomic analysis has greatly influenced the diagnosis, prognosis, and clinical management of patients with AML. Ongoing efforts to understand the genomic background of AML, including the mechanisms by which each mutation drives the disease phenotype and how these mutations interact with one another to affect risk of relapse, will be crucial, not only in risk stratification of AML, but also in developing novel targeted therapies and rational treatment combinations. Several mutations and chromosomal abnormalities have been identified that affect the prognosis of patients with AML.

AML Cytogenetic Risk Factors7

Risk Group Cytogenetic Abnormality
Favorable t(8;21)(q22;q22.1); RUNX1-RUNX1T1; inv(16)(p13.1q22) or t(16;16)(p13.1;q22);CBFB-MYH11; mutated NPM1 without FLT3-ITD or with FLT3-ITDlow; biallelic mutated CEBPA
Intermediate Mutated NPM1 and FLT3-ITDhigh; wild-type NPM1 without FLT3-ITD or with FLT3-ITDlow (without adverse-risk genetic lesions); t(9;11)(p21.3;q23.3); MLLT3-KMT2A; cytogenetic abnormalities not classified as favorable or adverse
Poor/Adverse t(6;9)(p23;q34.1); DEK-NUP214; t(v;11q23.3);KMT2A rearranged; t(9;22)(q34.1;q11.2); BCR-ABL1; inv(3)(q21.3;q26.2) or t(3;3)(q21.3;q26.2); GATA2,MECOM(EVI1); -5 or del(5q); -7; -17/abn(17p); complex karyotype; monosomal karyotype; wild-type NPM1 and FLT3-ITDhigh; mutated RUNX1; mutated ASXL1; mutated TP53


Although the number of mutations per AML genome or exome is lower than for most other cancers,8 with an average of only five recurrent mutations per AML genome, at least one driver mutation can be identified in 96% of patients with de novo AML, and 86% of patients have two or more driver mutations.9 Tremendous diversity exists in the overlap of these mutations and the subclonal genomic architecture of the disease. In addition to informing prognosis, some of these mutations serve as potential targets for AML directed therapies.10

The detection of chromosomal abnormalities by cytogenetic analysis is critically important in diagnosis and therapeutic decision-making in AML. Detection of t(8;21)(q22;q22.1), inv(16)(p13.1q22), t(16;16)(p13.1;q22), or translocations generating PML-RARA fusion transcripts allow the diagnosis of AML to be made even without the presence of ≥20% blasts.11 In addition, these specific cytogenetic alterations are associated with good prognosis among AML patients. In contrast, other cytogenetic abnormalities or a complex karyotype (defined as the presence of ≥3 cytogenetic abnormalities) are associated with adverse prognosis.12 However, a large proportion of patients do not bear these cytogenetic alterations and the identification that CEBPA, NPM1, and FLT3 internal tandem duplication (ITD) mutations predict response to induction and consolidation chemotherapy for cytogenetically normal AML patients younger than 60 years of age was a major advance in the last decade.13 This is particularly important given the frequency of these mutations. One of the most common genetic abnormalities found in AML is a constitutively activating mutation of the receptor tyrosine kinase FLT3. Approximately 23% of AML patients have an internal tandem duplication of FLT3 (FLT3-ITD), which is associated with potentially life-threatening leukocytosis, high relapse rates, and reduced overall survival. A less common mutation of the tyrosine kinase domain (FLT3-TKD) occurs in 7% of AML patients and it may confer a negative prognosis but to a lesser extent than the FLT3-ITD mutation.14

This cytogenetic data has been used to define two subtypes of AML: AML with mutated NPM1 and AML with biallelic CEBPA mutations. The favorable prognostic significance of mutated CEBPA appears limited to those patients with biallelic CEBPA mutations that lack FLT3 or NPM1 mutations.15 Similarly, the effects of mutant NPM1 are superseded by concurrent FLT3-ITD mutations, particularly when the FLT3-ITD allelic ratio is ≥50%.13,16 Several additional examples of concurrent additional genetic alterations impacting the outcome of established genetic predictors have been recognized recently in AML. One that is commonly recognized in clinical practice is the adverse prognostic impact of KIT mutations among patients with t(8;21) or inv(16)/t(16;16) AML.11,17


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