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Essay: Acute myeloid leukemia (AML)

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  • Published: 22 September 2015*
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Acute myeloid leukemia (AML) is a heterogeneous clonal disorder of hematopoietic stem/progenitor cells and is characterized by a differentiation arrest as well as the uncontrolled proliferation of immature myeloid cells (blasts). The heterogeneous nature of AML is reflected by specific abnormalities in morphology, immunophenotype, and AML specific molecular and cytogenetic abnormalities. AML is observed in approximately 15-20% of all pediatric leukemias1. To distinguish the different lineages from which AML originates, two classification systems have been developed; the older French-American-British (FAB) system and the newer World Health Organization (WHO) classification. The WHO classification, which takes in account chromosomal rearrangements but also clinical features, includes many of the criteria of the FAB system (Table 1). Both systems are based on morphology, cytochemistry and immunophenotype.
1.2 Genetics
To develop AML, at least two types of genetic events are required: a type-I aberration which leads to uncontrolled proliferation and/or survival of leukemic blasts and a type-II aberration which leads to impaired differentiation of the leukemic blasts2. Type-I aberrations are often activating mutations in signal transduction pathways, e.g. Fms-like tyrosine kinase 3 (FLT3), Wilms tumor 1 (WT1), neuroblastoma RAS viral (v-ras) oncogene homolog (NRAS), and protein tyrosine phosphatase, non-receptor type 11 (PTPN11). Type-II aberrations are often chromosomal rearrangements of fusion proteins that are characteristic for AML, e.g PML-RAR?? [t(15;17)], AML1-ETO [t(8;21)], CBFB-MYH11 [inv(16)/t(16;16)] and, 11q23/MLL-rearrangements3. In case no aberrations can be found using conventional karyotyping the AML is referred to as cytogenetically normal AML (CN-AML)4. AML cases that have no type-II aberrations depicted in figure 2B and which are not CN-AML are classified as Others. Figure 2 gives an overview of different recurrent type-I and type-II aberrations which can be found in pediatric AML.
Figure 1: Distribution of type-I and type-II aberrations in pediatric AML3
Table 1: World Health Organization (WHO) classification of AML and related neoplasms.
Acute myeloid leukemia with recurrent genetic abnormalities
AML with t(8;21)(q22;q22); RUNX1-RUNX1T1
AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11
APL with t(15;17)(q24.1;q21.1); PML-RARA
AML with t(9;11)(p22;q23); MLLT3-MLL
AML with t(6;9)(p23;q34); DEK-NUP214
AML with inv(3)(q21q26.2) or t(3;3)(q21;q26.2); RPN1-EVI1
AML (megakaryoblastic) with t(1;22)(p13;q13); RBM15-MKL1
Acute myeloid leukemia with gene mutations
AML with mutated NPM1
AML with mutated CEBPA
Acute myeloid leukemia with myelodysplasia-related features
Therapy-related myeloid neoplasms
Acute myeloid leukemia, not otherwise specified
AML with minimal differentiation (FAB M0)
AML without maturation (FAB M1)
AML with maturation (FAB M3)
Acute myelomonocytic leukemia (FAB M4)
Acute monoblastic/monocytic leukemia (FAB M5)
Acute erythroid leukemia (FAB M6)
Acute megakaryoblastic leukemia (FAB M7)
Acute basophilic leukemia
Acute panmyelosis with myelofibrosis
Myeloid sarcoma
Myeloid proliferations related to Down syndrome
Transient abnormal myelopoiesis
Myeloid leukemia associated with Down syndrome
Blastic plasmacytoid dendritic cell neoplasm
1.3 Prognosis
Survival rates have improved over the last decades to ~70% in most subgroups due to risk-adapted treatment based on cytogenetic aberrations and improved supportive care5.
Chromosomal rearrangements regarding fusion genes RUNX1-RUNX1T1, CBFB-MYH11, PML-RARA, and MLL-MLLT11 and NPM1-mutated AML and CEBPA double mutations have a favorable outcome3. Whereas AML with monosomy 7, monosomy 5, complex karyotype, NUP95-KDM5A and some MLL-rearranged cases have a poor outcome6. The clinical outcome of rearrangements with the Mixed Lineage Leukemia (MLL) gene on chromosome arm 11q23 depends on its partner gene. To date, more than 80 translocations partners have been described for the MLL gene and more translocations partners are found every year7,8. Other prognostic factors are white blood cell count at diagnosis (WBC), response to the first course of treatment, and FAB type5,9,10.
The overall survival of pediatric AML has improved but relapse is still the most important cause of death. Approximately 40% of the patients relapse after complete remission was achieved. In the last decades, overall survival after first relapse has improved from 20 to 40%11. Relapses occurs mainly in the bone marrow, but also in the central nervous system (CNS) and other extramedullary sites10. At present, the causes of therapy failure and relapse in pediatric AML are largely unknown.
1.4 Mixed Lineage Leukemia rearrangements in pediatric AML
Approximately 15 to 20% of all pediatric AML cases have a MLL rearrangement. Although the clinical outcome, in general, is poor, large difference in overall survival can be found between translocation partners (Figure 3)12. The MLL gene encodes a histone methyltransferase which plays an essential role in early development and hematopoiesis via regulation of gene expression, like homeobox (HOX) genes. Although almost 80 translocations partners are known, the most common MLL rearrangements are t(9;11)(p22;q23), t(10;11)(p12;q23), t(6;11)(q27;q23), and t(11;19)(q23;p13.1)7. MLL rearrangements are frequently classified as FAB-M4 and FAB-M5. Chromosomal translocations account for the majority of all MLL rearranged cases, however, other recurrent events have been found involving the MLL gene13.
Figure 2: Overall survival between different translocation partners of MLL. All subgroups contain at least 10 patients. Patients that could not be included in one of the subgroups were assigned to the ’11q23/MLL other’ group 12.
The MLL gene regulates the transcription of specific target genes by mediating chromatin modifications. Gene expression can also regulated via other mechanisms, like RNA processing and mRNA translation. Recently a new class of small, non-coding RNAs was found to regulate gene expression on a posttranscriptional level, called microRNAs.
1.5 MicroRNAs
MicroRNAs are small, non-coding RNAs that regulate gene expression by mRNA target cleavage, translational repression or mRNA deadenylation, thereby regulating protein synthesis and thus influencing cellular processes like proliferation, differentiation and apoptosis. Aberrant expression of microRNAs has been observed in various types of cancer, including leukemia, and microRNA signatures have even been defined that classify tumors14,15. In addition, genes that encode for microRNAs are often found in chromosomal regions that are deleted, amplified or involved in translocations in cancer16.
Although differences in microRNA biosynthesis exist, the ‘linear’ canonical pathway of microRNA processing is the most used pathway for mammalian microRNAs (Figure 4). In the nucleus, the primary microRNA transcript (pri-miRNA) is transcribed from a microRNA gene or intron by RNA polymerase II or III. The pri-miRNA is then cleaved by Drosha into a pre-miRNA or precursor hairpin which consists of a miRNA/miRNA* complex. This complex is then exported from the nucleus to the cytoplasm by Exportin-5. In the cytoplasm, the pre-miRNA is then cleaved into mature length microRNA by Dicer. The functional strand or guide strand (red), of the mature microRNA is loaded together with Argonaute (Ago2) proteins into the RNA-induced silencing complex (RISC), where it guides RISC to silence target mRNAs through mRNA cleavage, translational repression or deadenylation. The passenger strand or miRNA* (black) is degraded17. The thermodynamic stability of the microRNA duplex ends determines which strand of the complex is loaded into RISC18. Until recently, the miRNA* was considered to be less important because of the low concentrations of these microRNAs in the cell and also because miRNA* are rarely incorporated into the RISC complex19. It is thought that miRNA* function in the cell whiteout using the RISC complex. Instead of functional strand and miRNA*, -5p and -3p are now used as annotation to distinguish between the functional strand and miRNA*.
Figure 3: The “lineair’ canonical pathway for the biogenesis of microRNAs. A pri-microRNA is transcribed from a microRNA gene or intron by RNA pol II or III. The pri-microRNA is then cleaved by Drosher into a pre-microRNA which is transported from the nucleus to the cytoplasm by Exportin-5. In the cytoplasm, the pre-microRNA is cleaved by Dicer into a microRNA/miroRNA* complex. The functional strand (red) is then loaded into RISC, where it guides RISC to silence target mRNAs. The passenger strand (black) is degraded.
1.6 MicroRNA gene location
MicroRNAs are the fine tuners of gene expression and deregulation of microRNAs is found in human cancers. MicroRNAs can influence many cellular processes, like cell growth, apoptosis and, cell cycle control because a single microRNA can target many genes. MicroRNAs can also function, just as protein coding genes, as an oncogene or tumor suppressors, although this is determined by cell type and physiological context20.
Almost half of the microRNA genes are located in clusters through the human genome21. The majority of the microRNA genes are located in intergenic regions and most of the other microRNA genes are located in intronic regions. MircoRNA genes that are located intergenic are transcribed as independent transcription units and intronic microRNA genes are transcribed as part of the protein coding gene in which they are located22. Clusters of microRNA genes compose of multiple microRNAs which are transcribed from the genome as one pri-miRNA and cleaved by Drosha into single pre-miRNAs. The miR-17~92 cluster is one most studied microRNA cluster and which may function as an oncogene23. The miR-17~92 cluster has two paralogs, miR-106b~25 and miR-106a~363, which are located on chromosome 7 and chromosome X, respectively. The three microRNA clusters share a sequence homology between 50-90% and as a result may target, in some extent, the same mRNA targets21.
MicroRNA-106b~25 cluster
The miR-106~25 cluster is overexpressed in various cancer types and is a bad prognostic factor in prostate and endometrial cancer24. The miR-106b~25 cluster consists of three mature microRNAs; miR-106b, miR-93, and miR-25. In gastric cancer, these microRNAs silence two main downstream effectors of the Transforming Growth Factor ?? Tumor Suppressor Pathway (TGF ??): the cell cycle inhibitor CDKN1A (p21) and the proapoptotic gene BCL2L11 (BIM)24. Overexpression of this cluster may be a consequent of amplification of the MCM7 gene, in which this cluster is located, or due to overexpression of transcriptional regulators such as MYC, MYCN, and AIB-125. The MCM7 gene is essential for the initiation of eukaryotic genome replication and ensuring that all the genome is replicated once per cell cycle26.

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