Introduction
Phenotypically and genetically diverse, acute myeloid leukemia (AML) is a category of hematological illnesses defined by an aberrant increase of blast cells in the bone marrow and peripheral circulation. In children, AML accounts for 15–20% of all occurrences of acute leukemia, but in grown-ups, it represents 80% of all cases (Kantarjian et al., 2021). Based on cytogenetic markers, patients are typically classified as having a favorable, intermediate, or unfavorable risk.
In addition to traditional molecular markers, the discovery of various genetic mutations has helped discover novel organisms. The diagnosis, prognosis, and treatment of AML now involve many mutations and epigenetic abnormalities. It is expected that new medications will be developed and existing anti-leukemic agents will be used rationally once the significance of gene mutations in leukemogenesis is understood.
Molecular Structure
DNA and RNA are the most crucial macromolecules in cell biology since they are accountable for storing and decoding the genetic codes necessary for all life. The two are linear molecules consisting of phosphates, bases, and sugars, but there are noteworthy differences between them. These distinctions make it feasible for the two polymers to cooperate and execute their vital functions.
DNA has a double helix structure with two separate strands; nucleotides are the building blocks for these strands (Varshney et al., 2020). A single nucleotide encompasses a nitrogenous base, a 5-carbon sugar molecule, and a phosphate. Although both RNA and DNA are composed of nucleotides, the former has a single strand while the latter has a double-stranded helix.
In comparison to RNA, DNA is a very long polymer. For example, a chromosome is a single, incredibly long DNA molecule that, if unrolled, would stretch for many centimeters. The length of RNA molecules varies, but they are always substantially shorter than DNA polymers (Varshney et al., 2020). The average size of an RNA molecule is merely a few thousand base pairs.
Unlike ribose, the sugar in DNA (deoxyribose) is missing a hydroxyl group. Sugar molecules called ribose are found in RNA but lack the hydroxyl groups in deoxyribose. DNA contains four different building blocks called bases: thymine (‘T’), guanine (‘G’), adenine (‘A’), and cytosine (‘C’). Similar to DNA, RNA comprises the nucleobases guanine (‘G’), adenine (‘A’), and cytosine (‘C’) but also uracil (‘U’) instead of thymine.
The nucleic acids DNA and RNA share three of their four nitrogenous bases. Nucleotides, the central building blocks of DNA and RNA, are structurally identical. They all have the same three components: a phosphate group, a sugar molecule, and a nitrogenous base. Phosphodiester linkages connect the 3′ carbon of one monomer to the 5′ carbon of the next in DNA and RNA (Varshney et al., 2020). The backbone is formed of sugar and phosphate in both cases.
Transcription and Translation
Cells employ the two-step procedure of transcription and translation to read every gene and generate the amino acids that constitute a protein. In the nucleus, the transcription process converts the DNA sequence of genes into a molecule called messenger RNA (mRNA). The mRNA is transported out of the nucleus and used as a template for DNA translation (Varshney et al., 2020). The cell controls the pace of genetic expression by modulating nuclear mRNA synthesis.
The translation process involves the ribosome reading the mRNA sequence and converting it into the protein’s amino acid sequence. The ribosome reads three nucleotides simultaneously, beginning at the AUG sequence. The three nucleotides that make up a codon designate a certain amino acid. The ribosome knows the protein is complete when it encounters the ‘stop’ codons (UAA, UAG, and UGA).
Leading and Lagging Strands
First in the fundamental dogma is DNA replication, the process by which copies of the DNA strands are created. When two DNA strands divide, they form a replication fork, where copies of both strands are made. Contrary to a leading strand that replicates continually, a lagging strand is copied in chunks, creating smaller pieces.
The lagging strand is the one that unwinds from 3′ to 5′, away from the replication fork (Varshney et al., 2020). The strand moves from 5′ to 3′ in the replication fork, called the leading strand. DNA ligase enzymes are required to join small Okazaki fragments in lagging strands, but are not necessary for leading strands.
AML Running in Families
Familial AML is a subtype of hereditary leukemia passed down dominantly via families. Certain hereditary disorders can raise the likelihood of developing AML. If an identical twin has AML within the first year of life, both will likely get the condition. In the first year of infancy, the incidence of AML for identical twins of a parent with AML is considerably greater than that for the broader population, but it reduces to practically zero thereafter. Thisprovides evidence that environmental factors are far more crucial than genetic factors in the onset of AML.
Since their genetics are identical, and their environmental factors are similar, if not the same, it is a biological puzzle why only one identical twin will acquire leukemia. A higher risk of developing acute lymphoid leukemia and AML has been linked to Down syndrome, a genetic disorder present from birth (DiNardo & Lachowiez, 2019). Myelodysplastic syndrome and AML are common in people with congenital neutropenia (a low number of germ-eliminating white blood cells) at birth. Bone marrow failure from Fanconi anemia, which can be hereditary or present at birth, frequently leads to AML.
Genes Tested
Mutations in genes, as well as translocations and inversions, are of prognostic significance in AML. Molecular alterations have been linked to the etiology of AML alongside significant chromosomal rearrangements (Kantarjian et al., 2021). The risk assessment and prognosis of some individuals with AML can be improved with a complete review of many molecular markers, such as FLT3, NPM1, CEBPA, KIT, IDH1, and IDH2. In addition, molecular genetic studies on leukemia cells can be utilized to determine whether a patient requires intensive chemotherapy or a stem cell transplant. Such examinations aim to detect ‘sub-microscopic alterations’ in the underlying genetic material.
People with the FLT3 mutation are more likely to experience a recurrence of their malignancy despite receiving treatment. After the initial full remission, stem cell/bone marrow transplantation might extend the lives of children with this kind of AML (DiNardo & Lachowiez, 2019). New medications targeting FLT3-positive cells are being studied to see whether they can improve leukemia treatment. Researchers have shown that nucleophosmin-1 (NPM1) and CEBP mutations in childhood leukemia cells are associated with a better prognosis (chance of recovery) than abnormalities in other genes. If these alterations are present in leukemia, chemotherapy alone may be recommended rather than a stem cell transplant.
Conclusion
In AML, myeloid precursor cell clonal proliferation with impaired differentiation potential characterizes this group of phenotypically and genetically diverse hematological disorders. DNA polymerase drives polymerization in only one orientation, from 5′ to 3′; consequently, replication is uninterrupted in a leading strand whenever the template proceeds in the same direction. DNA polymerase disengages from the lagging strand at each fork and attaches to the newly synthesized strand since it is rushing out from the replication fork. RNA polymerase converts DNA to mRNA through the mechanism of transcription. Along with significant chromosomal reshuffles, molecular alterations have been associated with the genetic causes of AML.
References
DiNardo, C., & Lachowiez, C. (2019). Acute myeloid leukemia: From mutation profiling to treatment decisions. Current Hematologic Malignancy Reports, 14(5), 386-394. Web.
Kantarjian, H., Kadia, T., DiNardo, C., Daver, N., Borthakur, G., Jabbour, E., Garcia-Manero, G., Konopleva, M., & Ravandi, F. (2021). Acute myeloid leukemia: Current progress and future directions. Blood Cancer Journal, 11(2), 1-25. Web.
Varshney, D., Spiegel, J., Zyner, K., Tannahill, D., & Balasubramanian, S. (2020). The regulation and functions of DNA and RNA G-quadruplexes. Nature Reviews Molecular Cell Biology, 21(8), 459-474. Web.