Abstract
Acute myeloid leukemia (AML) is a clonal disorder affecting pluripotent stem cells and is characterized by ineffective hematopoiesis. Most AML patients harbor cytogenetic and molecular defects that identify entities with peculiar biologic and clinical data and distinct therapeutic responses. Approximately 50%–60% of de novo AML and 80%–95% of secondary AML patients display chromosomal aberrations. Structural chromosomal rearrangements are the most common cytogenetic abnormalities in de novo AML, with an incidence of 40%. Last years, large collaborative studies have demonstrated the importance of cytogenetic aberrations for the prognosis of AML patients.
Keywords
- AML
- mutations
- prognosis
- FLT3
- NPM1
- DNMT3A
- IDH1/2
1. Introduction
Acute myeloid leukemia (AML) is the most common type of leukemia among hematologic malignancies in adults. In the last years, progresses in molecular technologies have led to identify AML as a highly heterogeneous disorder. AML is a clonal hematopoietic disease that arises from multiple acquired genetic lesions accumulating in hematopoietic progenitors. The mutations give rise to a malignant clone [1]. In the initial development, Knudson’s two-hit hypothesis has provided important insights into the pathogenesis of leukemia. Later studies using mouse models have confirmed that genetic abnormalities in leukemia could be divided into two classes. Class I mutations confer a proliferative or survival advantage to blast cells, while class II mutations block myeloid differentiation and give self-renewability [2-4]. Recently, next-generation sequencing methods provided more complete insight in oncogenic events. Early mutations may be present many years before disease develops [5]. Evidence from many murine models has confirmed that early mutations lead to clonal expansions by progenitor cells. Later, cooperating mutations would arise in cells that already contain initiating early mutations [6].
Karyotype analysis allows detecting genetic changes on a chromosomal level by visual assessment of chromosomal banding. Recurrent chromosomal abnormalities are found in about 55% of adults with AML. Some, not all, of the chromosomal aberrations are strong independent predictors of outcome and are the mainstay of the World Health Organization (WHO) classification of AML risk groups [7]. In AML patients with cytogenetically normal karyotype (CN AML) who have an intermediate-risk cytogenetics, clinical outcomes vary greatly. Identification of recurrent mutations in AML improved the understanding of the molecular pathogenesis. Later studies revealed recurrent genetic markers in more than 85% of CN AML patients [8]. Some of the mutations add important prognostic information and also indicate potential therapeutic targets. The more detailed insight into the genetic architecture of AML is challenging the established classification and prognostication systems [8]. Particular mutations have already been included in the latest WHO classification that was established in 2008 and in subsequent recommendations for diagnosis of AML by an international expert panel [9].
2. Nucleophosmin 1 (NPM1 ) mutations
The nucleophosmin/nucleoplasmin (NPM) family of chaperones has diverse functions in the cell. The
In AML, there are some chromosomal translocations involving
Mutations in the
The prognostic status of
3. FLT3 mutations in AML
The
The binding with ligand activates the FLT3 protein, which subsequently activates a series of proteins inside the cell that are part of multiple signaling pathways and leads to receptor oligomerization and transphosphorylation of specific tyrosine residues, which activates the downstream signaling pathways including STAT5, RAS/mitogen-activated protein kinase, and phosphatidylinositol 3-kinase/AKT. The signaling pathways stimulated by the FLT3 protein control many important cellular processes such as the growth, proliferation, and survival of cells, particularly of hematopoietic progenitor cells [32, 33].
The
Two predominant types of
The second type of
Specific gene expression signatures have been reported for CN AML with both
Sequencing studies show that
In addition,
Recent studies also show that both the
The prevalence and prognostic implications of
4. CCAAT/Enhancer-Binding Protein α (C/EBPα ) mutations
The
When
There is evidence that C/EBPα mutations are early events in the generation of leukemic clones. In contrast to
Three different
Expression profiling revealed that
Most patients with
The prognostic impact of
5. RUNX1 mutations
The runt-related transcription factor 1 (
The reported incidence of
6. RAS mutations
The
Mutations in
Despite being initially described almost 30 years ago, the prognostic implications of RAS mutations remain controversial. Several studies indicate that
No association
7. KIT (CD117) mutations
The
Ligand-independent activation of
The clinical significance of
8. TET2 mutations
The TET (ten–eleven translocation) protein family includes three members (TET1, TET2, and TET3) and is involved in the epigenetic regulation, in particular, responsible for demethylation.
Several studies based on mouse model suggested that
This could indicate of a cooperative mechanism through which mutations impairing DNA hydroxymethylation and DNA methylation contribute to leukemogenesis [118].
The prognostic relevance of
In addition, recently demonstrated low levels of
9. IHD1 and IDH2 mutations
Isocitrate dehydrogenases (IDH) 1 and 2 are NADP-dependent enzymes of the citrate cycle that convert isocitrate to α-ketoglutarate.
Somatic mutations in
The typical
In AML,
10. DNMT3A mutations
Somatic mutations in the
The biology of
Since the
Several studies reported a negative prognostic impact of
Some authors have found stability of
Recent discoveries utilizing whole-exome sequencing in a large cohort of persons unselected for cancer or hematologic phenotypes have demonstrated somatic mutations in significant proportion of persons particularly older than 65 years. Moreover,
11. Conclusion
The whole gene analysis has revealed that leukemic cell carry hundreds of mutated genes. Most of them are “passenger” mutations, which do not provide a selective advantage, and a less number of mutations are “driver” mutations. The latter can cause the tumor. The simultaneous presence of genetic alterations with different functional effects on hematopoietic progenitors led to the concept of leukemogenesis as a multi-step process that ultimately gives rise to malignant transformation. Evidence from many murine models confirmed that a single genetic change is not sufficient for the occurrence of AML. Moreover, two modern studies have demonstrated that somatic mutations that drive clonal expansion of blood cells were a common finding in the elderly and most frequently involved
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