The Role of Epithelial-to-Mesenchymal Transition Transcription Factors (EMT-TFs) in Acute Myeloid Leukemia Progression

Abstract

Acute myeloid leukemia (AML) is a diverse malignancy originating from myeloid progenitor cells, with significant genetic and clinical variability. Modern classification systems like those from the World Health Organization (WHO) and European LeukemiaNet use immunophenotyping, molecular genetics, and clinical features to categorize AML subtypes. This classification highlights crucial genetic markers such as FLT3, NPM1 mutations, and MLL-AF9 fusion, which are essential for prognosis and directing targeted therapies. The MLL-AF9 fusion protein is often linked with therapy-resistant AML, highlighting the risk of relapse due to standard chemotherapeutic regimes. In this sense, factors like the ZEB, SNAI, and TWIST gene families, known for their roles in epithelial-mesenchymal transition (EMT) and cancer metastasis, also regulate hematopoiesis and may serve as effective therapeutic targets in AML. These genes contribute to cell proliferation, differentiation, and extramedullary hematopoiesis, suggesting new possibilities for treatment. Advancing our understanding of the molecular mechanisms that promote AML, especially how the bone marrow microenvironment affects invasion and drug resistance, is crucial. This comprehensive insight into the molecular and environmental interactions in AML emphasizes the need for ongoing research and more effective treatments.

Keywords: AML classification; MLL-AF9 fusion; epithelial–mesenchymal transition (EMT); extramedullary engraftment; genetic aberrations in AML; hematopoietic stem cells; therapy-resistant AML.

Figure 1

Anticancer drugs can interfere with the catalytic cycle of TOP2, causing chromosomal translocation. (1) DNA supercoiling and catenation. (2) TOP2 dimer binds to one DNA double helix (green), and some compounds can inhibit TOP2 binding to DNA [111]. (3,4) Top2 generates a double-strand break in green DNA in the presence of Mg²⁺, and TOP2 remains attached to both DNA ends. A second DNA double helix (red) passes through the break in an ATP-dependent process. Some compounds can stimulate or inhibit DNA break formation [111]. (5–7) After the red DNA passage is completed, green DNA is re-ligated and both DNAs are released from the enzyme. (5a) Etoposide and doxorubicin can inhibit DNA re-ligation [111], resulting in the accumulation of TOP2 attached to DNA ends. After proteasomal action, DNA with double-strand breaks is repaired by Non-Homologous End-Joining (NHEJ), potentially leading to mutation (6a) or chromosome translocation (6b) [19].

Figure 2

Overview of the role of EMT factors in normal hematopoiesis, AML development, and EME. EMT factors such as ZEB2 ensure hematopoietic lineage fidelity during early hematopoiesis by restraining mature gene expression programs. Later in hematopoiesis, EMT factors lock in cell identity once committed. Upregulated expression of ZEB2 can specifically transform T cell lineage and cause Early T cell Precursor Acute Lymphoblastic Leukemia (ETP-ALL). AML driver mutations can increase EMT factor expression, including ZEB1/2, SNAI1/2, and TWIST1, which can corrupt epigenetic factors such as LSD1 and lead to leukemic stem cell (LSC) gene expression program and transformation. EMT factors can also enhance survival signal pathway expression and increase drug resistance. EMT processes also drive extramedullary tissue engraftment, tissue colonization, and blast crisis development by altering AML cell adhesion and homing and survival signals. Ery—erythrocyte, Meg—megakaryocyte, Mac—macrophage, Gr—granulocyte, DC—dendritic cell, NK—natural killer cells, B—B cells, T—T cells, EME—extramedullary engraftment, HSC—hematopoietic stem cell, HPC—hematopoietic progenitor cell, LSC—leukemic stem cell.