Investigating the Genetic and Epigenetic Determinants of Acute Myeloid Leukemia (AML) Pathogenesis


Despite the fact that acute myeloid leukemia is a rare illness, it is linked with high mortality and morbidity. Microscopic and molecular sequencing approaches may be used to identify cytogenetic and molecular abnormalities specific to this organism. In high-income nations, these genetic testing are essential for diagnosis and prognosis. As a result, treatment may be tailored to each patient’s specific needs. Many people in the UK do not have access to these tests. Hence no data has been collected on this group of individuals. All patients diagnosed with acute myeloid leukemia in the UK’s adult hemato-oncology units have to be screened for chromosomal abnormalities and molecular alterations. The research used a cross-sectional descriptive study with sequential sampling. A total of 10 study participants were selected from among those who satisfied the eligibility requirements and gave their approval or agreed to participate. Metaphase G-banding and next-generation sequencing were performed on peripheral blood samples. The clinical and laboratory data and the patient’s social and demographic characteristics were entered into a research proforma. Due to a tiny sample size, no descriptive analysis was performed. Tables were used to display descriptive statistics. The Ampliseq for Illumina myeloid panel was used to conduct cytogenetic analysis and next-generation sequencing on ten individuals. The findings of cytogenetic investigations were not conclusive. Mutations were found in 29 of the most frequently mutated genes. A mutation has been found. Three patients with TP53 mutations fit the criteria for the ELN group. AML patients at certain UK hospitals were found to contain harmful mutations that provide each patient with a unique genetic spectrum and contribute to the variety of illness outcomes across patients, according to the findings of this research. It is impossible to determine the prognostic value of these mutations without cytogenetic investigation and the following outcomes.



1.1 Background of the study

Acute myeloid leukemia (AML) is a kind of leukemia that originates from stem and progenitor cells in the bone marrow (Li et al., 2016). These cells undergo continual genetic and epigenetic evolution and clonal diversity as part of their malignant transformation. As a result, AMLs include a wide variety of malignant cell types. Because of the large number of cytogenetic and somatic mutations seen in leukemia subclone cells, the genomes of these cancers are very difficult to unravel (Puumala et al., 2019).

It has been more than a decade since Ley et al. (2008) revealed the first complete genome sequencing of acute myeloid leukemia (AML). Molecular profiling and risk stratification of patients using next-generation sequencing technologies based on the presence of somatic mutations seen in leukemia have become standard and fundamental parts of AML diagnosis since then (Cai and Levine, 2019). Newly diagnosed or relapsed AML patients may benefit from this mutational data, especially because new targeted medicines for FLT3 and IDH1/2 have been authorized for patients carrying these mutations (Krishnan et al., 2022). Sequencing in the AML sector has yielded a wealth of information regarding the disease’s mutational and clonal complexity and the pre-leukaemic phases currently known as clonal hematopoiesis (Krishnan et al., 2022). As these studies have shown, epigenetic aberrations have also been shown to be quite common in AML.

Genes that control the normal hematopoietic process are altered in acute myeloid leukemia cells in a way specific to this disease (Krishnan et al., 2022). This explains the disease’s wide range of phenotypes (Sadikovic et al., 2008). As a result of understanding the underlying biology of AML, new treatment techniques with individualization and identification of post-treatment minimum residual illness have been developed. Fifty percent of people under the age of 60 and 20 percent of people over the age of 60 have a five-year survival rate of 50 percent and 20 percent for people who have cancer (Carr and Patnaik, 2020). A groundbreaking new anti-leukemic treatment should be able to destroy the malignant founder clone and its sub-clones, eliminating a possible niche for recurrence. Clinical characteristics, cytochemical tests, bone marrow specimen morphological evaluation, cytogenetic testing, immunophenotyping, and molecular testing are used to identify separate biological subgroups with clinical significance in the WHO classification of AML (Thomas et al., 2016). Sub-groups of AML include Undifferentiated acute myeloblastic leukemia, Acute myeloblastic leukemia with minimal maturation, Acute myeloblastic leukemia with maturation, Acute promyelocytic leukemia (APL), Acute myelomonocytic leukemia, Acute myelomonocytic leukemia with eosinophilia, Acute monocytic leukemia, Acute erythroid leukemia, and Acute megakaryoblastic leukemia. Myelodysplastic-related changes, myeloid neoplasms linked to treatment, AML that is not already described, myeloid sarcoma, and myeloid proliferations linked to the down syndrome are all in the 2016 WHO classification of AML.

In the past, the morphological description of acute leukemias was used to classify them based on the predominant cell type in the bone marrow population and its relationship to the cell’s normal equivalent. Only a few cytochemical methods, such as enzyme localization, micro-spectrophotometry, micro-incineration, radioautography, and cryo-electron microscopy, were used to enhance the light microscopic examination of regularly stained blood and marrow smears in this approach. The etiology, morphology, immunophenotyping, and cytogenetics committees of the World Health Organization developed a categorization system in 2001 that differentiates between AML and other myeloproliferative illnesses (Bakhshi and Georgel, 2020). When 20% or more of the nucleated marrow cells are blast cells, AML is diagnosed. Distinct morphological subtypes and clinical profiles are linked to specific abnormalities. Translocations of chromosomal DNA usually cause these cytogenetic anomalies, which result in the novel (abnormal) protein products from the fusion genes that arise. The cellular dysregulation that results in cancer is thought to be caused by the protein products of these fusion genes (Lauschke et al., 2019). Chromosome abnormalities such as AML are vital in selecting treatment plans and have generated significant independence. Several genes, including FLT3, CEBPA, KIT, ERG, MLL, BAALC, and NPM1, have been associated with a more favorable prognosis in AML patients (Crowther et al., 2008).

Through the activation of signalling pathways, these alterations promote haematopoietic progenitor proliferation and survival. RUNX1, CEBPA, and RARA are transcription factors affected by the second class of mutations (Milosevic and Kralovics, 2013). The accumulation of immature progenitors is hampered by mutations or translocations that impact these processes. The frequent detection of mutations in each of these groups in AML led Gilliland and Griffin to propose a “double-hit” model of leukemogenesis (Milosevic and Kralovics, 2013). They argue that either mutation may malignantly transform hematopoietic stem cells. If both a class I and class II mutation were present, leukemia would arise. It is true that not all AMLs include mutations that exactly match these two kinds of alterations; hence, the double-hit model has certain limitations. According to recent epigenomic research, the epigenetic and transcriptional programming effects generated by combining class I and II mutations were shown to be unique from those caused by each mutation alone (Baylin and Jones, 2016).

Studies have shown that chromosomal abnormalities in AML have a consistent prognostic value, and cytogenetic analysis should be conducted on all newly diagnosed patients (Baylin and Jones, 2016; Puumala et al., 2019; Bakhshi and Georgel, 2020; Krishnan et al., 2022). As a result, in many facilities, post-remission treatment strategies strongly depend on cytogenetic analysis results. Cytogenetic data has been utilized for molecular breakpoint mapping, enabling the use of more sensitive methods such as fluorescence in situ hybridization and primers for reverse transcriptase polymerase chain reaction to be employed. It is important to note that these procedures are not employed for general screening or detailed assessment from the outset (Crowther et al., 2008).

From the earliest stages of life to old age, acute myeloid leukemia (AML) affects people of all ages. However, cases are gradually increasing (Sugimura and Ushijima, 2000). AML is rare cancer, accounting for about 1% of all cancer cases. About 20,050 persons of all ages have been diagnosed with AML in the United States in 2021, 11,140 men and boys and 8,910 women and girls (Cancer.net Editorial Board, 2022). Among adults and children, AML is the second most often diagnosed form of leukemia. This thesis aims to understand better how genetic and epigenetic heterogeneity occurs in acute myeloid leukemia (AML), if and how they are connected, and what they contribute to the illness from a clinical perspective.

1.2 Statement of the problem

Despite the fact that treatment outcomes have improved over time, acute myeloid leukemia (AML) still ranks as one of the main causes of mortality (Izzo and Landau, 2016). Despite advancements in treatment-associated mortality, chemo-resistance and post-transplant disease recurrence continue to be among the most challenging aspects of AML management. This heterogeneous clonal illness is the result of successive genetic and epigenetic changes in a malignant myeloid stem cell (Izzo and Landau, 2016). The genetic modifications these cells have undergone interrupt the normal hematological process, causing the formation of aberrant, poorly differentiated neoplastic cells in the blood and bone marrow (Li et al., 2018).

The World Health Organization recommends genetic testing for all individuals with acute myeloid leukemia. Since it is an expensive and crucial examination, many individuals in the UK cannot afford it. This is a group of young, healthy individuals who may benefit from treatment that is individualized for their particular risk.

As a starting point, this research encourages the development of risk-based therapy for a wider sample of patients, which might lead to better outcomes.

1.3 Rationale

Myeloid leukemia is a fatal condition spreading across the United Kingdom (Shah and Rawal, 2019). Numerous studies have shown a connection between various anomalies and acute myeloid leukemia (Zhou et al., 2013; Sun et al., 2018; Shah and Rawal, 2019). Patients who get chemotherapy and have inherited genes have a poor prognosis because of increased cell proliferation brought on by unchecked activation of tyrosine kinase receptors (KIT D816). In spite of the fact that there have been published studies pertaining to this association, our study will be carried out in the UK to find the KIT D816 polymorphism and its relationship with acute myeloid leukemia patients’ prognosis.

This research concentrated on where genetic and epigenetic variability meets in AML. When it comes to epigenetic modifier genes, we are going to focus on the effect of mutations that arise early in the illness and may drastically alter the cell’s epigenome and epigenetic landscape, thereby generating a functional connection between genetic and epigenetic diversity.


Bakhshi, T.J. and Georgel, P.T., 2020. Genetic and epigenetic determinants of diffuse large B-cell lymphoma. Blood cancer journal, 10(12), pp.1-23.

Baylin, S.B. and Jones, P.A., 2016. Epigenetic determinants of cancer. Cold Spring Harbor perspectives in biology, 8(9), p.a019505.

Baylin, S.B. and Jones, P.A., 2016. Epigenetic determinants of cancer. Cold Spring Harbor perspectives in biology, 8(9), p.a019505.

Benetatos, L., Dasoula, A., Hatzimichael, E., Syed, N., Voukelatou, M., Dranitsaris, G., Bourantas, K.L. and Crook, T., 2011. Polo-like kinase 2 (SNK/PLK2) is a novel epigenetically regulated gene in acute myeloid leukemia and myelodysplastic syndromes: genetic and epigenetic interactions. Annals of hematology, 90(9), pp.1037-1045.

Bravo, G.M., Lee, E., Merchan, B., Kantarjian, H.M. and García‐Manero, G., 2014. Integrating genetics and epigenetics in myelodysplastic syndromes: advances in pathogenesis and disease evolution. British journal of haematology, 166(5), pp.646-659.

Cai, S.F. and Levine, R.L., 2019, April. Genetic and epigenetic determinants of AML pathogenesis. In Seminars in haematology (Vol. 56, No. 2, pp. 84-89). WB Saunders.