Version May 2024
INTRODUCTION — Acute myeloid leukemia (AML) develops as the consequence of a series of genetic changes in a hematopoietic precursor cell. These changes alter normal hematopoietic growth and differentiation, resulting in an accumulation of large numbers of abnormal, immature myeloid cells in the bone marrow and peripheral blood. These cells are capable of dividing and proliferating, but cannot differentiate into mature hematopoietic cells (ie, neutrophils).
This topic will review the cell of origin and the multistep and multicausal pathogenesis of AML. More detailed descriptions of the molecular basis of AML and the genetic abnormalities seen in AML are presented separately, as is a discussion of familial acute leukemia and myelodysplastic syndromes. (See "Acute myeloid leukemia: Molecular genetics" and "Acute myeloid leukemia: Cytogenetic abnormalities" and "Acute myeloid leukemia: Risk factors and prognosis" and "Familial disorders of acute leukemia and myelodysplastic syndromes".)
CELL OF ORIGIN
Normal counterpart — Leukemia is a heterogeneous group of diseases characterized by clonal cells that exhibit maturation defects that correspond to stages in hematopoietic differentiation. Hematopoietic stem cells are multipotent and have the capacity to differentiate into the cells of all 10 blood lineages — erythrocytes, platelets, neutrophils, eosinophils, basophils, monocytes, T and B lymphocytes, natural killer cells, and dendritic cells. In order to sustain hematopoiesis, stem cells are part of a developmental hierarchy capable of three basic functions:
●Maintenance in a non-cycling state (ie, not actively progressing through the cell cycle)
●Self-renewal, allowing production of additional stem cells
●Production of committed progenitor cells
These progenitor cells commit to subsets of myeloid and lymphoid lineages, and ultimately to single developmental pathways, resulting in the expression of the terminally differentiated stage of each cell type (figure 1) [1,2]. (See "Overview of hematopoietic stem cells".)
Normal hematopoiesis is a dynamic, highly regulated process controlled by the combined effects of growth factors that permit cellular proliferation, and nuclear transcription factors that activate specific genetic programs, resulting in commitment to a specific lineage and in terminal differentiation (figure 2). Many of the regulatory growth factors and a number of specific transcription factors have been identified that play critical roles in lineage commitment, and in the subsequent development of the mature lymphoid and myeloid (erythroid, granulocytic/monocytic, and megakaryocytic) lineages [3,4].
A number of genes encoding these transcription factors are involved in recurring chromosomal translocations seen in AML, suggesting that the AML variants arise because the translocations result in significant alterations in regulatory processes controlling growth and differentiation programs [5]. The novel fusion genes created by these translocations will be reviewed separately. (See "Acute myeloid leukemia: Molecular genetics".)
Clonality — AML is a clonal process that develops from a single transformed hematopoietic progenitor cell. Virtually all cases of AML are thought to be preceded by a premalignant proliferative disorder characterized by clonal hematopoiesis without other evidence of a malignancy [6-8]. Such clonal hematopoiesis of indeterminate potential (CHIP) increases in association with age and most commonly involves a mutation in DNMT3A, TET2, or ASXL1 (mutations that are associated with myeloid malignancies). While clonal hematopoiesis was associated with an increased risk of hematologic cancer, the absolute risk of progression is small. (See "Clonal hematopoiesis of indeterminate potential (CHIP) and related disorders of clonal hematopoiesis".)
Evidence for clonal hematopoiesis has also been demonstrated using biochemical assays of X-linked enzyme isoenzymes (eg, glucose-6-phosphate dehydrogenase [G6PD]), standard cytogenetics, recombinant DNA probes, and fluorescence in situ hybridization (FISH) [9-14].
Leukemic stem cells — AML is a heterogeneous disease with leukemic cells of different subtypes resembling normal cells at various stages of maturation. However, there is growing information to support that all leukemias, including AML, appear to be maintained by a pool of self-renewing malignant cells. Based on their ability to serially transfer the disease upon xenotransplantation into immunodeficient mice, it has been hypothesized that limited numbers of cells within the bulk population of leukemic cells have the capacity to function as stem cells that maintain the potential for unlimited self-renewal [15]. These leukemic stem cells (LSC, also leukemia-initiating cells) may be more immature than the majority of circulating leukemic cells and are thought to have originated from cells with existing self-renewal capacity or from progenitors that have re-acquired this stem cell-like property.
According to this hypothesis, the majority of leukemia cells do not have unlimited self-renewal and exhibit some features of partial differentiation depending on the genetic aberration present. However, xenotransplantation of human leukemia cells might not be the best experimental system to examine leukemia stem cell capacity. When lymphomas and leukemias of mouse origin are transplanted into histocompatible mice, a very high frequency (at least 1 in 10) of these cells can transfer the disease to recipient mice suggesting that the low frequency of leukemia-initiating cells observed in xenotransplantation studies may reflect the limited ability of human tumor cells to adapt to growth in a foreign (mouse) milieu [16].
Stage of leukemic transformation
Two models have been proposed to explain the heterogeneity of AML observed at the molecular, cytogenetic, phenotypic, and clinical level.
●Transformation to leukemia occurring at one of several developmental stages
●Transformation to leukemia occurring within primitive multipotent cells
There is no universal agreement as to which of these two models best reflects the truth.
Transformation at one of several developmental stages — This model proposes that any cell type within the stem cell/progenitor cell hierarchy, from primitive multipotent stem cell to lineage-committed progenitor cell, is susceptible to leukemic transformation, resulting in the expansion of abnormal cells that exhibit different stages of differentiation. For AML, this model predicts that the phenotype of the leukemic stem cells restricted to the granulocytic-monocytic series differs from that of cells in the erythroid or megakaryocytic lineages (figure 1).
The correlation between specific cytogenetic and molecular genetic aberrations and the morphologic appearance of leukemic cells might suggest that the transforming event occurs at different stages of myeloid differentiation. This hypothesis is underscored by the classification for AML, which distinguishes some subtypes of AML based upon the stage of apparent differentiation (eg, AML with minimal differentiation). Support for this model includes flow cytometric/molecular analyses of the leukemic cell in acute promyelocytic leukemia (APL) that suggest that the leukemic cell arises in a committed lineage-restricted, CD34+/CD38+ progenitor cell [17].
Transformation within primitive multipotent cells — A second model proposes that mutations responsible for leukemic transformation and progression occur only in primitive multipotent stem cells, with disease heterogeneity resulting from a variable ability of these primitive stem cells to differentiate and acquire specific phenotypic lineage markers [18,19].
Hematopoietic stem cells express a characteristic cell surface antigen (CD34), and can be further subdivided by the expression of additional cell surface antigens, including CD38 and HLA-DR [20,21]:
●CD34+/CD38-/HLA-DR- cells are multipotential hematopoietic stem cells, give rise to mixed-lineage granulocytic-erythroid-megakaryocytic colonies in culture, can repopulate immune deficient mice with normal hematopoietic cells in vivo, and demonstrate self-renewal capacity, as assessed by their ability to be serially transplanted into recipient mice. There are data to suggest that, in some cases of AML, the leukemic stem cell may be quite similar to normal hematopoietic stem cells [22].
●CD34+/CD38+/HLA-DR+ cells define a committed population of myeloid progenitor cells [23]. (See "Overview of hematopoietic stem cells".)
Cytogenetic and FISH studies of sorted stem cell compartments from patients with AML evolving from a prior myelodysplastic syndrome and patients with de novo AML have shown that the characteristic cytogenetic abnormality from both groups was present in the CD34+/CD38- multipotential stem cell compartment [24-26]. Similar findings were noted in patients with the 5q- syndrome [27] and monosomy 7 [28], myelodysplastic disorders with differing risks of leukemic transformation. (See "Clinical manifestations, diagnosis, and classification of myelodysplastic syndromes (MDS)".)
More compelling evidence comes from studies in which purified stem cell subpopulations from normal subjects and those with AML were transplanted into mice with severe combined immunodeficiency disease (SCID) [29]. These experiments have detected approximately one SCID mouse leukemia-initiating cell (SL-IC) in 105 AML cells, which can repopulate immune deficient mice with leukemic cells phenotypically identical to those of the AML patient from which they were derived [26,29,30].
Using a non-obese diabetic (NOD)/SCID mouse [31], SL-ICs were found to reside only in the CD34+/CD38- fraction [15]. This was consistent regardless of the AML subtype, lineage markers, or percentage of leukemic blast cells expressing the CD34 antigen. The SL-ICs also demonstrated self-renewal capacity, a requirement for maintenance of the leukemic clone. The uniformity of the leukemic stem cell phenotype strongly suggests that the leukemia initiating transformation and progression-associated genetic events occur in primitive cells and not in committed progenitors. Similar conclusions about the site of the leukemia initiating transformation have been made in acute lymphoblastic leukemia [32].
Additional evidence for the second model derives from the use of a retroviral gene transfer system to express AML1/ETO, a fusion gene linked to the pathogenesis of AML, in normal human hematopoietic stem and progenitor cells [33]. When this fusion gene was expressed in more mature progenitor cells, the result was growth arrest and abrogated colony formation in primary clonogenic assays. On the other hand, AML1/ETO expression in stem cells resulted in their preferential expansion and/or self-renewal [34]. (See "Acute myeloid leukemia: Molecular genetics", section on 'Cooperating mutations in AML'.)
Further supporting evidence comes from studies of clonal hematopoiesis in AML, which indicate that, although the majority of cells derived from the leukemic clone can undergo differentiation to cells of the granulocytic-monocytic lineage, they also may differentiate into cells of the erythroid and/or megakaryocytic pathways [12-14,35]. Such multi-lineage involvement has been noted more frequently in older patients, in secondary AML that arose from myelodysplastic syndrome, or following treatment for another malignancy [14,35].
Protection by stromal cells — AML cells develop in the bone marrow where interaction with the microenvironment may foster chemoresistance [36-39]. As an example, two studies in mouse models of APL demonstrated that dislodgement of leukemic cells from their stromal environment via interruption of CXCR4 signaling resulted in an increased sensitivity of the leukemic cells to chemotherapy [40,41]. Other studies have suggested that this abnormal microenvironment is at least partially due to leukemic cell growth that disrupts normal hematopoietic progenitor cell niches in the bone marrow [37,42].
Suppression of normal hematopoiesis — Pancytopenia is common among patients with AML and many patients initially present with symptoms related to complications of leukopenia, anemia, and thrombocytopenia. Historically, pancytopenia in AML has been attributed to the leukemic cells either displacing or killing normal hematopoietic stem cells in the bone marrow. However, subsequent studies suggest that, in patients with AML, the number of normal hematopoietic stem cells in the bone marrow is normal or increased [43]. Instead, the leukemic cells appear to inhibit the ability of the hematopoietic stem cells to produce more mature hematopoietic cells. When the stem cells were removed from the leukemic environment the ability to produce mature hematopoietic cells was restored.
Aberrant cellular metabolism — Altered cellular metabolism is a hallmark of cancer and may contribute to AML initiation and maintenance [44-46].
As an example, up to 15 to 20 percent of patients with AML have mutations in IDH1 or IDH2 that result in neomorphic enzymatic activity and production of the onco-metabolite, 2-hydroxyglutarate (2HG) from alpha-ketoglutarate [44]. 2HG inhibits multiple alpha-ketoglutarate-dependent dioxygenase reactions, leads to aberrant DNA hypermethylation and a differentiation block in myeloid precursors, and promotes leukemogenesis. Allosteric inhibitors of the mutant IDH isoforms, ivosidenib (IDH1) and enasidenib (IDH2) can overcome the differentiation block and have been approved for treatment.
TWO-HIT HYPOTHESIS OF LEUKEMOGENESIS — Progression to acute leukemia may require a series of genetic events beginning with clonal expansion of a transformed leukemic stem cell [47-49]. The specific mutational event(s) required for this progression are not currently well defined. Single nucleotide polymorphism (SNP) studies have been performed on tumor samples from adults and children with AML as a genomic screen to locate previously unidentified genes that may play a role in the pathobiology of AML [50,51].
The "two-hit hypothesis" of leukemogenesis implies that AML is the consequence of at least two mutations, one conferring a proliferative advantage (class I mutations) and another impairing hematopoietic differentiation (class II mutations) [52]. Type I mutations include those of FLT3-ITD, K-RAS mutations, and KIT mutations, while mutations in CEBPA are type II abnormalities [53]. (See "Acute myeloid leukemia: Risk factors and prognosis".)
Important insights have been obtained from human leukemias:
●In chronic phase chronic myeloid leukemia (CML), all leukemic cells contain t(9;22), resulting in formation of the BCR/ABL fusion gene [54], whose product is of critical significance in the pathogenesis of CML [55]. As the disease progresses, additional cytogenetic abnormalities are acquired [56], which are often accompanied by loss of important tumor suppressor genes such as p53 [57]. (See "Cellular and molecular biology of chronic myeloid leukemia", section on 'The BCR-ABL1 fusion protein' and "Cellular and molecular biology of chronic myeloid leukemia", section on 'Progression to acute phase CML'.)
●A variety of clonality studies have shown that patients with AML in clinical remission may still have clonal, rather than polyclonal, hematopoiesis [12,58-60]. Such clonal remission may represent the presence of a "preleukemic stem cell" that has undergone an initial transforming event but has not acquired the additional mutation(s) essential to progression to overt leukemia. In these cases, it is presumed that the transformed, overtly leukemic cell probably represented a subclone of the original "preleukemic stem cell" which secondarily acquired the additional genetic mutations required for the definitive block in differentiation and manifestation of the leukemic phenotype. Although some studies suggest that "clonal" remissions may be the result of skewed Lyonization (preferential inactivation of one X chromosome over another) [61,62], more carefully controlled studies suggest that clonal remissions do occur following treatment for AML [63,64].
●On average, AML clones have 8 to 13 mutations found within the coding regions of the genome. The accumulation of these lesions in a step-wise process within a hematopoietic stem cell was demonstrated in a study that analyzed gene mutations found in primary tumor-relapse pairs of de novo AML and patient-matched skin samples [65]. Identification of individual cells containing subsets of these mutations allowed for the identification of mutations that occurred early and late in the process. This finding suggests not only that several hits are required for the development of AML, but also that relapsed disease can represent the further replication of the original dominant clone, the emergence of a minor clone present at diagnosis [66,67], or further evolution of a preleukemic clone after treatment (figure 3).
●Whole genome or whole exome sequencing of 200 cases of de novo AML reported an average of 13 gene mutations per tumor [68]. Of these, each tumor had an average of five genes known to be one of a group of 23 genes recurrently mutated in AML that can be broadly grouped into nine categories of genes thought to be involved in leukemogenesis. Mutations were found in genes associated with transcription-factor fusions (18 percent), nucleophosmin (27 percent), tumor suppression (16 percent), DNA-methylation (44 percent), signaling (59 percent), chromatin-modification (30 percent), myeloid transcription factor (22 percent), the cohesin-complex (13 percent), and the spliceosome complex (14 percent). Some mutation pairs occurred more commonly than expected (eg, NPM1 and FLT3), suggesting synergy, while others were mutually exclusive, suggesting duplicative pathways. (See "Acute myeloid leukemia: Molecular genetics", section on 'Gene mutations'.)
●In one study of seven patients with AML that had evolved from myelodysplastic syndrome, approximately 85 percent of bone marrow cells were clonal at the time of myelodysplastic syndrome diagnosis [69]. Whole genome sequencing of paired skin and bone marrow samples identified 11 recurrently mutated genes. Genotyping of bone marrow samples from the same patients collected at the time of AML diagnosis identified those mutations that were present at the time of myelodysplastic syndrome diagnosis (ie, NPM1, RUNX1, SMC3, STAG2, TP53, U2AF1, UMODL1, and ZSWIM4) and those that developed subsequently (ie, CDH23, PTPN11, WT1).
A retrospective study that compared mutational analyses of paired diagnostic and relapse leukemia samples from 69 children with AML reported that 38 percent of patients had a change in their mutation status between diagnosis and relapse. Patients whose AML demonstrated a type I/II mutation at relapse had a shorter time to relapse. Consistent with the two-hit theory, expression of a chimeric protein represents only one of the genetic modifications necessary for the development of cancer and leukemia, and that the affected cell requires additional mutational events in order to express the transformed phenotype. (See "Acute myeloid leukemia: Cytogenetic abnormalities", section on 't(8;21); RUNX1::RUNX1T1'.)
As an example, a number of examples indicate that the presence of cells with the RUNX1/RUNX1T1 fusion transcript may not be sufficient, in itself, to result in AML:
●Transgenic mice expressing RUNX1/RUNX1T1 were healthy throughout their lifespan, developing AML only after exposure to an alkylating mutagen [70], or in cooperation with Wilms tumor gene (WT1) overexpression [71].
●Remission bone marrow samples from patients with de novo AML (FAB -M2) with t(8;21)(q22;q22) and the RUNX1/RUNX1T1 fusion transcript have been found to harbor the aberrant fusion transcript for as many as eight years following cessation of all chemotherapy [72].
●The RUNX1/RUNX1T1 fusion transcript has been detected in bone marrow samples from patients in remission following allogeneic bone marrow transplantation for AML [73].
●In five children who developed AML with t(8;21) at 3 to 12 years of age, in whom archived blood samples for metabolic studies (Guthrie cards) were available, RUNX1/RUNX1T1 sequences were detected at birth [74]. Of interest, similar observations were made in three children developing acute lymphoblastic leukemia at three to five years of age with t(12;21) [75].
As noted above, RUNX1/RUNX1T1 is not immediately leukemogenic in either animals or man, and may require a "second hit" for the development of AML [76,77]. However, the presence of an alternatively spliced isoform AML1/ETO9a has been shown to be present in the majority of patients with t(8;21) [78]. Expression of this alternative isoform leads to the rapid development of leukemia in a mouse model, and coexpression of RUNX1/RUNX1T1 and AML1/ETO9a results in the substantially earlier onset of AML and blocks myeloid cell maturation at a more immature stage. These early results suggest that fusion proteins from alternatively spliced isoforms resulting from a chromosomal translocation may work together to induce this malignancy.
MECHANISMS OF GENETIC DAMAGE — Genetic changes associated with leukemogenesis can occur following chemotherapy, ionizing radiation, chemical exposure, and infection with retroviruses. In addition, certain familial disorders are associated with an increased incidence of AML.
While environmental and hereditary conditions serve as excellent models for obtaining insights into the molecular pathogenesis of AML, it must be emphasized that the vast majority of patients with de novo AML show no evidence of any of these risk factors, and the etiologic factors contributing to the development of AML remain unknown. Interestingly, in a series of 127 patients with a previous primary malignancy and secondary AML, 30 percent did not receive any chemotherapy or radiation treatment prior to the development of AML [79].
Chemotherapy-induced AML — The development of myelodysplastic syndromes (MDS) and AML following chemotherapy for a variety of malignancies (eg, breast cancer, Hodgkin lymphoma) is an unfortunate complication of curative treatment strategies [80], such as dose-intensive therapy with or without hematopoietic cell transplantation and growth factor support [80-84]. This identification of an increasing incidence of therapy-related AML (t-AML) in an attempt to improve cure rates emphasizes the critical importance of understanding the underlying pathogenetic mechanisms for development of t-AML [85,86]. (See "Secondary cancers after hematopoietic cell transplantation" and "Second malignancies after treatment of classic Hodgkin lymphoma", section on 'Acute leukemia' and "Overview of long-term complications of therapy in breast cancer survivors and patterns of relapse", section on 'Risks associated with chemotherapy'.)
t-AML typically develops following alkylating agent-induced damage, at a median of three to five years following therapy for the primary malignancy and is usually associated with an antecedent myelodysplastic disorder [87]. This latency period suggests that multiple mutational events are involved in the development of the malignant phenotype [47].
●Clonal chromosomal abnormalities have been reported in the majority of cases of t-AML (see "Acute myeloid leukemia: Cytogenetic abnormalities", section on 'Therapy-related myeloid neoplasms'). The most frequently reported abnormalities involve complete loss or interstitial deletions of the long arm of chromosomes 7 and/or 5.
●Other therapy-related leukemias are associated with rearrangements of the MLL gene in chromosome band 11q23 [88]. AML associated with 11q23 often develops after treatment with drugs that target DNA-topoisomerase II (eg, epipodophyllotoxins, anthracyclines) with a very short latency of 12 to 18 months following treatment, and are not typically associated with an antecedent MDS [89-91]. (See "Acute myeloid leukemia: Molecular genetics", section on 'Involvement of the KMT2A (MLL) locus' and "Acute myeloid leukemia: Cytogenetic abnormalities", section on 't(9;11); KMT2A::MLLT3'.)
●Accelerated telomere loss may precede the development of t-MDS/AML after autologous hematopoietic cell transplantation resulting in genetic instability and thereby contributing to the leukemic transformation [92,93].
Genetic polymorphisms of a number of drug-metabolizing enzymes may alter the risk of t-AML [86,94,95]. As an example, polymorphisms in genes that encode glutathione S-transferases (GST), which detoxify potentially mutagenic chemotherapeutic agents, may increase susceptibility to t-AML as well as MDS [94,96,97]. In one study, relative to de novo AML, the GSTP1 codon 105 Val allele occurred more often among patients with t-AML with prior exposure to chemotherapy, particularly those with exposure to known GSTP1 substrates (odds ratio 4.3; 95% CI 1.4-13), and not among those t-AML patients with prior exposure to radiotherapy alone.
Ionizing radiation — Ionizing radiation shares with alkylating agents the ability to damage DNA, usually by inducing double strand breaks that may cause the mutations, deletions, or translocations required for hematopoietic stem cell transformation [80,98]. As examples, an increased incidence of AML, which may have been directly proportional to the radiation exposure [99], has been noted in atomic bomb survivors [100] as well as in radiologists and radiologic technologists chronically exposed to high levels of radiation in the period before 1950 [101].
Ionizing radiation used in the treatment of malignancies (eg, Hodgkin lymphoma, breast cancer, uterine cancer, lung cancer) has also been linked to the development of AML [102]. This risk appears to be quite low when radiation alone is used as treatment, and is associated with age of the patient, and doses of more than 20 Gy [103,104]. Whether irradiation adds to the risk of t-AML associated with chemotherapy remains controversial. Although some studies suggest that the risk of development of AML is significantly increased when the two modalities are combined, other studies demonstrated that high doses of radiotherapy confined to small volumes in combination with chemotherapy did not significantly increase leukemogenic risk [105-108].
It is unknown whether ionizing radiation used for medical examination, such as computed tomography (CT) scans, results in an increased risk of leukemia in adults. However, there is epidemiologic evidence that exposure to x-rays and gamma rays during childhood is associated with a small absolute increase in the incidence of leukemia. In a cohort study of individuals who had CT scans when they were younger than 22 years of age, compared with those who received a cumulative radiation dose <5 mGy, the risk of subsequent leukemia was tripled for those who received a cumulative radiation dose ≥30 mGy, which is equivalent to approximately 5 to 10 head CT scans [109]. Radiation risk in children is compounded with their longer lifespan following exposure so that there is a longer time over which radiation-induced cancers can occur.
Chemical exposure — Exposure to high levels of benzene has been associated with a higher risk of developing AML [110,111]. Relatively low-level exposure to benzene by petroleum distribution workers has been associated with an increased risk of developing MDS, but not AML [112,113]. The risk of developing a myeloid malignancy after benzene exposure appears to be dose-related and it is unknown whether there is any safe threshold for benzene exposure [114-116]. A potential association between formaldehyde exposure and AML has been controversial, with conflicting data from meta-analyses of epidemiologic studies [117-120]. Except for special groups exposed to high levels of benzene or radiation, the reported risks associated with occupation and chemicals have generally been less than twofold [121].
The presence of RAS mutations in patients with AML has been associated with specific occupational exposure to chemicals, suggesting that these exposures may induce genetic damage culminating in acute leukemia [122]. In a case-control study, cigarette smoking was associated with only a modest increase in leukemic risk; however, a twofold increase in risk for AML was noted in study subjects over the age of 60 [123].
Polymorphisms resulting in inactivation of NAD(P)H:quinone oxidoreductase 1 (NQO1, originally called DT-diaphorase), an enzyme which detoxifies quinones and reduces oxidative stress, have been associated with an increased risk of de novo [124] and therapy-related acute leukemia [125], as well as a greater risk of benzene-induced hematotoxicity and leukemia [126]. For de novo AML, the most significant effect of low or null NQO1 activity was observed among patients with chromosomal translocations and inversions (odds ratio: 2.4), and was especially high for those with inv(16) (odds ratio: 8.1) [124].
Genetic polymorphisms in the microsomal epoxide hydrolase (HYL1) gene, an enzyme involved in benzene metabolism, have also been associated with an increased incidence of AML. Data from one study suggest that smoking and/or exposure to a carcinogen that is activated by HYL1, such as benzene, may be important in subsets of patients with AML, such as males with t(8;21) or -7/del(7q) [127,128].
Infections — Patients with AML often have infections at the time of diagnosis, some of which are severe. However, there are limited data regarding whether infections play a role in the pathogenesis of AML. A large population-based retrospective registry study from Sweden suggested that a personal history of infection was associated with an increased risk of developing AML or myelodysplastic syndrome [129]. While interesting, further study is needed to confirm these results and to study potential mechanisms. Studies have also suggested that chronic acetaminophen use might increase the risk of developing AML [130,131].
In a number of animal models, retroviruses have been demonstrated to play an important role in leukemogenesis, and the human T-lymphotropic virus type I (HTLV-I) is associated with adult T cell leukemia-lymphoma [132]. In AML, however, despite extensive investigation, there has been no clear association of a retrovirus with leukemogenesis [133]. (See "Acute myeloid leukemia: Molecular genetics", section on 'Animal models of AML' and "Clinical manifestations, pathologic features, and diagnosis of adult T cell leukemia-lymphoma".)
Familial acute leukemia and myelodysplasia syndromes — Most patients diagnosed with AML do not have a clear familial predisposition towards the development of MDS or leukemia [134]. However, rare pedigrees with multiple cases of AML have been described and termed familial leukemia. Familial leukemia can occur in the context of a medical syndrome in which AML is one component of the overall disease, or it can occur as an isolated leukemia not specifically associated with co-morbid conditions [135]. Inherited disorders associated with defective DNA repair have also been associated with a high incidence of hematologic malignancies, including AML. The adoption of next-generation sequencing technologies has facilitated the rapid discovery of an increasing number of mutations associated with familial leukemia predisposition syndrome [136]. Familial acute leukemia and myelodysplastic syndromes are discussed in more detail separately. (See "Familial disorders of acute leukemia and myelodysplastic syndromes".)
ROLE OF HEMATOPOIETIC GROWTH FACTORS — Using in vitro clonogenic assays, leukemic cells have been shown to proliferate in response to many of the endogenous hematopoietic growth factors critical for normal hematopoiesis, including granulocyte, granulocyte-monocyte, macrophage, and stem cell colony-stimulating factors (G-CSF, GM-CSF, M-CSF, SCF), interleukin 3, and Flt3 ligand (flt3-L) [137-142], with combinations of these factors producing a synergistic growth response.
Mutations in the G-CSF receptor gene — Mutations in the granulocyte colony-stimulating factor (G-CSF) receptor gene have been described in patients with severe congenital neutropenia [143]. A number of patients with severe congenital neutropenia with documented nonsense mutations in the G-CSF receptor have developed AML, supporting the notion that defective signaling function by the aberrant receptor increased the susceptibility to AML [144]. It is also possible that mutations in the G-CSF receptor predispose to the myelodysplastic syndrome (MDS) [145], or to AML via a resistance to apoptosis [146], allowing more time for a "second hit" mutation to occur. (See "Congenital neutropenia".)
In a substantial number of patients with AML, autonomous growth has been reported to occur as a result of autocrine or paracrine stimulation by a number of factors, including G-CSF, GM-CSF, IL-1b, and IL-6 [147,148]. Several investigators have noted that the presence of autonomous growth characteristics by AML cells grown in vitro correlates with lower remission rates, and poor survival [149,150]. In a multivariate analysis, expression by leukemic blasts of c-mpl, the receptor for thrombopoietin, correlated with a significantly decreased remission duration in patients with AML [151].
Several explanations for these observations have been proposed. One possibility is that the acquisition of autonomous growth capability allows AML cells to become more aggressive, by making them independent of stromal cell production of essential growth factors [150]. Others have suggested that autonomous production of growth factors, such as GM-CSF, may reduce the cytotoxicity of chemotherapy agents, by altering intracellular drug metabolism [152]. Some data suggest that exogenously administered, as well as endogenously produced, hematopoietic growth factors not only stimulate in vitro growth and proliferation, but also inhibit apoptosis of AML cells [153,154].
As a result of in vitro data demonstrating the growth-promoting effects of a variety of cytokines on AML cells, one of the controversies in the treatment of AML has centered on the use of hematopoietic growth factors during or following induction chemotherapy. The desired goal of reducing the toxicity of treatment and the duration of cytopenia with exogenous administration of G-CSF or GM-CSF has been tempered by concerns about their leukemogenic potential. A number of large, randomized clinical trials in AML demonstrate variable clinical efficacy of these growth factors with respect to significant decreases in morbidity and mortality [155]. While different conclusions have been reached regarding clinical efficacy, there is consensus about the safety and lack of increased leukemogenic potential of these growth factors when they are administered following induction or consolidation chemotherapy. Although similar theoretical arguments have been made against the use of growth factors in MDS, they appear to be safe and have a role in the treatment of selected patients. (See "Myelodysplastic syndromes/neoplasms (MDS): Management of hematologic complications in lower-risk MDS", section on 'Thrombocytopenia'.)
Exogenous growth factors — The therapeutic use of granulocyte colony-stimulating factor (G-CSF) may result in an increased risk of AML or MDS, although the magnitude of the risk appears to be small and may be dose related. Initial suggestions of this association came from retrospective analyses and prospective trials mostly involving its use in breast cancer [156,157]. A systemic review which included data from 12,104 patients enrolled in randomized controlled clinical trials of cancer chemotherapy with G-CSF reported the following at a median follow-up time of 54 months [158]:
●The estimated relative risk for AML/MDS among patients assigned to receive G-CSF was 1.9 with an absolute increase in risk of 0.4 percent.
●The estimated relative risk for mortality among patients assigned to receive G-CSF was 0.9 with an estimated absolute decrease of 3.4 percent.
Despite a suggested increased risk of AML/MDS among patients receiving G-CSF, patients who received G-CSF demonstrated superior survival. By its nature, this analysis of randomized trials avoids many of the potential biases that confound the earlier retrospective studies; however, this study design cannot differentiate between an increase in rates of AML/MDS due to the use of G-CSF versus an increase due to the use of dose-intensified systemic chemotherapy. Further studies are required to address this issue. (See "Acute myeloid leukemia: Cytogenetic abnormalities", section on 'Therapy-related myeloid neoplasms'.)
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 5th to 6th 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 10th to 12th 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 info" and the keyword(s) of interest.)
●Beyond the Basics topics (see "Patient education: Acute myeloid leukemia (AML) treatment in adults (Beyond the Basics)")
SUMMARY
●Acute myeloid leukemia (AML) develops as the consequence of a series of genetic changes in a hematopoietic precursor cell. These changes alter normal hematopoietic growth and differentiation, resulting in an accumulation of large numbers of abnormal, immature myeloid cells in the bone marrow and peripheral blood. These cells are capable of dividing and proliferating, but cannot differentiate into mature hematopoietic cells (ie, neutrophils).
●AML is a heterogeneous group of diseases characterized by clonal cells that exhibit maturation defects that correspond to stages in hematopoietic differentiation. (See 'Cell of origin' above.)
●All leukemias, including AML, appear to be maintained by a pool of self-renewing malignant cells. These leukemic stem cells (also leukemia-initiating cells) may be more immature than the majority of circulating leukemic cells and are thought to have originated from cells with existing self-renewal capacity or from progenitors that have reacquired this stem cell-like property. (See 'Leukemic stem cells' above.)
●The "two-hit hypothesis" of leukemogenesis implies that AML is the consequence of at least two mutations, one conferring a proliferative advantage (class I mutations) and another impairing hematopoietic differentiation (class II mutations). (See 'Two-hit hypothesis of leukemogenesis' above.)
●Leukemogenic mutations can occur following chemotherapy, ionizing radiation, chemical exposure, and infection with retroviruses. In addition, certain familial disorders are associated with an increased incidence of AML. (See 'Mechanisms of genetic damage' above.)
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