The Role of Epithelial-to-Mesenchymal Transition Transcription Factors (EMT-TFs) in Acute Myeloid Leukemia Progression
Abstract
:1. Definition of Acute Myeloid Leukemia (AML), Genetic Variability, and Classification
2. MLL-AF9 Fusion Protein Oncogenic Mechanisms and Incidence in AML
3. First-Line Treatments for AML May Cause t(9;11)—A Mechanistic Perspective
4. Emergence of Epithelial-to-Mesenchymal Transition (EMT) Factors in the Risk and Progression of AML: The Role of ZEB Transcription Factors
5. Role of ZEB Transcription Factors
6. Role of SNAI Transcription Factors
7. LSD1 and Other Potential Therapeutic Targets
8. Role of SNAI2 in AML
9. Role of TWIST1 in AML
10. Spread of AML Cells
11. Intravasation and Extravasation Mechanisms of AML
12. Overall Conclusions and Future Directions
Author Contributions
Funding
Conflicts of Interest
Abbreviations
AML | acute myeloid leukemia |
WHO | World Health Organization |
MLL-AF9 | Mixed-Lineage Leukemia-AF9 fusion protein |
EMT | epithelial-to-mesenchymal transition |
EMT-TFs | epithelial-to-mesenchymal transition transcription factors |
FAB | French–American–British |
APL | Acute Promyelocytic Leukemia |
PML-RARα | Promyelocytic Leukemia-Retinoic Acid Receptor Alpha |
ATRA | all-trans retinoic acid |
ATO | arsenic trioxide |
MDS | myelodysplastic syndrome |
TP53 | Tumor Protein 53 |
ELN | Elastin |
HSCs | hematopoietic stem cells |
BM | bone marrow |
PB | peripheral blood |
RUNX1::RUNX1T1 | Runt-Related Transcription Factor 1–RUNX1 Translocation Partner 1 |
CBFB::MYH11 | Core-Binding Factor Beta Subunit–Myosin Heavy Chain 11 |
BCR::ABL1 | Breakpoint Cluster Region–Abelson Tyrosine Kinase 1 |
CEBPA | CCAAT/Enhancer Binding Protein Alpha |
VAF | variant allele fraction |
MLLT3 | MLLT3 super elongation complex subunit |
NMR | nuclear magnetic resonance |
H3K4 | histone H3 lysine 4 |
HSPCs | hematopoietic stem and progenitor cells |
DOT1L | Disruptor of Telomeric Silencing 1-Like Protein |
ETO | RUNX1 partner transcriptional co-repressor 1 |
TOP2 | Topoisomerase II |
DSBs | double-strand breaks |
NSCLC | Non-Small Cell Lung Cancer |
WBCs | White Blood Cells |
AKT/mTOR | AKT Serine/Threonine Kinase/Mechanistic Target of Rapamycin |
ZEB | Zinc Finger E-Box Binding Homeobox |
CTBP | C-Terminal Binding Protein |
SLc13A3 | Solute Carrier Family 13 Member 3 |
CD36 | Cluster of Differentiation 36 |
THBS1 | thrombospondin 1 |
IL-17 | Interleukin 17 |
SOCS2 | Suppressor of Cytokine Signaling 2 |
TGF-β | Transforming Growth Factor Beta |
CXCR4 | C-X-C Motif Chemokine Receptor 4 |
CDH2 | cadherin 2 |
LOX | Lysyl Oxidase |
COL3A1 | Collagen Type III Alpha 1 Chain |
MRTF-SRF | Myocardin-Related Transcription Factors and Serum-Response Factor |
SDF-1 | Stromal Cell-Derived Factor 1 |
CXCL12 | C-X-C Motif Chemokine Ligand 12 |
NPM1 | Nucleophosmin 1 |
FLT3-ITD | Fms-Like Tyrosine Kinase 3-Internal Tandem Duplication |
LDH | Lactate Dehydrogenase |
LDHA | Lactate Dehydrogenase A |
SF3B1 | splicing factor 3b subunit 1 |
circRNAs | Circular RNAs |
MALAT1 | Metastasis-Associated Lung Adenocarcinoma Transcript 1 |
Hox | Homeobox |
LSD1 | lysine-specific demethylase 1 |
GFI1 | Growth Factor Independent 1 |
miRNA | microRNA |
CRISPR/Cas9 | Clustered Regularly Interspaced Short Palindromic Repeats/CRISPR Associated Protein 9 |
lncRNA | long non-coding RNA |
TGF | Transforming Growth Factor |
CD8 | Cluster of Differentiation 8 |
TGF-β | Transforming Growth Factor Beta |
VEGF | Vascular Endothelial Growth Factor |
SETDB1 | SET Domain Bifurcated Histone Lysine Methyltransferase 1 |
N-WASP | Neural Wiskott–Aldrich Syndrome Protein |
Tks4 | Tyrosine Kinase Substrate With Four SH3 Domains |
Tks5 | SH3 and PX Domains 2A Protein |
G-CSF | Granulocyte Colony-Stimulating Factor |
IL-6 | Interleukin 6 |
LDS1 | lysine-specific histone demethylase 1A |
GATA2 | GATA Binding Protein 2 |
MECOM | MDS1 and EVI1 Complex Locus |
DEK | DEK oncogene |
NUP214 | Nucleoporin 214 |
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Subtype | Characteristics | Prognosis and Features |
---|---|---|
M0 | High percentage of minimally differentiated blasts, negative for peroxidase, confirmed with myeloid markers by flow cytometry. | Poor prognosis, associated with complex chromosomal abnormalities. |
M1 | Less than 10% promyelocytes, blasts lack granules with distinct nucleoli, >3% positive for myeloperoxidase. | |
M2 | Presence of mature cells, including cells with Auer rods, associated with t(8;21) translocations and AML1-ETO/ETO-AML1 fusion proteins. | More favorable prognosis when linked with specific translocations. |
M3 (APL) | Hypergranulated promyelocytes, bilobed nuclei, characterized by the PML-RARα fusion from t(15;17) translocation. Treatable with ATRA and arsenic trioxide (ATO). | Favorable prognosis due to effective treatment options. |
M4 | Presence of monocytes and promonocytes in bone marrow. The M4Eo variant shows abnormal eosinophils and inv(16) cytogenetic abnormality. | Favorable prognosis for variants like M4Eo depending on WBC levels. |
M5 | High number of monocytic lineage cells, over 30% blast cells in BM or PB, often associated with 11q abnormalities and MLL gene rearrangements (e.g., MLL-AF9). | Poor prognosis, common extramedullary disease, and linkage to severe clinical features. |
M6 | Over 50% nucleated erythroid cells in bone marrow with substantial abnormalities, positive for PAS staining and glycophorin A. | Rare, less than 5% of AML cases, associated with severe developmental abnormalities in erythroid cells. |
M7 | Poor megakaryocytic differentiation, megakaryoblasts with scant cytoplasm and dense chromatin, negative for common stains, confirmed by CD41 and electron microscopy. | Extremely rare (~1% of cases), poor prognosis due to aggressive nature and difficulty in treatment due to morphological variability in the cells. |
AML Type | Blast % | Genetics | ELN Risk Class (2022) | Literature (2024) | Refs. |
---|---|---|---|---|---|
APL with t(15;17)/PML::RARA | >10% | PML:RARA | - | Favorable | [33,34] |
APL with other RARA rearrangements | >10% | Various RARA rearrangements | - | Variable, depends on the rearrangement | [35] |
AML with t(8;21)/RUNX1::RUNX1T1 | >10% | RUNX1:RUNX1T1 | Favorable | Favorable | [36] |
AML with inv(16) or t(16;16)/CBFB::MYH11 | >10% | CBFB:MYH11 | Favorable | Favorable | [37,38] |
AML with t(9;11)/MLLT3::KMT2A | >10% | MLLT3:KMT2A | Intermediate | Intermediate | [39] |
AML with other KMT2A rearrangements | >10% | Various KMT2A rearrangements | - | Variable, depends on the rearrangement | [39] |
AML with t(6;9)/DEK::NUP214 | >10% | DEK:NUP214 | Adverse | Adverse | [40] |
AML with inv(3) or t(3;3)/GATA2; MECOM | >10% | GATA2; MECOM | Adverse | Adverse | [41] |
AML with other MECOM rearrangements | >10% | Various MECOM rearrangements | - | Adverse | [42] |
AML with other rare recurring translocations | >10% | Rare recurring translocations | - | Adverse | [43] |
AML with t(9;22)/BCR::ABL1 | >10% | BCR:ABL1 | Adverse | Adverse | [44] |
AML with mutated NPM1 | >10% | Mutated NPM1 | Favorable | Favorable | [45] |
AML with bZIP CEBPA mutations | >10% | bZIP CEBPA mutations | Favorable | Favorable | [46] |
AML/MDS with mutated TP53 | 10–19%/>20% | Mutated TP53 | Adverse | Adverse | [47] |
AML/MDS with myelodysplasia-related gene mutations | 10–19%/>20% | Myelodysplasia-related gene mutations | - | Adverse | [48] |
AML with myelodysplasia-related cytogenetic abnormalities | 10–19%/>20% | Myelodysplasia-related cytogenetic abnormalities | - | Intermediate | [49] |
AML not otherwise specified (NOS) | 10–19%/>20% | - | - | - | [50] |
Myeloid sarcoma | Not specified | - | Adverse | Adverse | [51] |
MDS with mutated TP53 | 0–9% | Multi-hit TP53 mutation or TP53 mutation (VAF > 10%) and complex karyotype often with loss of 17p | Adverse | Adverse | [29,30] |
MDS/AML with mutated TP53 | 10–19% | Any somatic TP53 mutation (VAF > 10%) | Adverse | Adverse | [29,30] |
AML with mutated TP53 | >20% | Any somatic TP53 mutation (VAF > 10%) | Adverse | Adverse | [29,30] |
Feature | ZEB1 | ZEB2 | SNAI1 | SNAI2 | TWIST1 |
---|---|---|---|---|---|
Roles in EMT Processes | Involved in malignant dissemination and metastasis [116,117] | Plays a role in cancer or tumor stem cell properties, development, and treatment resistance [118,119] | Essential for EMT, cancer stemness, and drug resistance [155,156,157] | Promotes leukemogenesis and influences chemotherapy resistance [170,171] | Central to AML pathophysiology; affects growth and drug resistance [172] |
Roles in Hematopoiesis | Lesser degree of influence compared with ZEB2 [129,130] | Limits inappropriate expression of immune cell programs [131,132,133,134] | Influences stem and progenitor cell functions [158] | Impairs LSC self-renewal, restricts LSC self-renewal via Slc13a3 [170] | Impacts progenitor clonogenic capacities [175] |
Regulation by the MiR200 Family of miRNAs | Negatively regulated, lower levels in certain AML subtypes [138] | Negatively regulated; absence leads to oncogenic levels [138,139,140] | Relationship in hematopoiesis is unclear [158] | Not specified | Not specified |
Influence on AML Patient Outcomes | Associated with poor outcomes, essential for leukemic blast invasion [117,130] | Upregulation associated with leukemic blasts [130] | Overexpression contributes to impaired differentiation and enhanced self-renewal [163] | Associated with poor clinical outcomes [171] | Linked to poor prognostic factors; promotes tissue invasion [172,174] |
Oncofusion Protein Interactions | Upregulated by MLL-AF9 and MLL-AF4 [117] | Upregulated by AML-ETO, MLL-AF9, MLL-AF4, and PML-RARα [116,117] | Not clear | Not specified | Notably involved in extramedullary manifestations [174] |
Genetic Screening Findings | Deletion may accelerate AML progression [129,130] | Involved in myeloid and lymphoid leukemic transformation [120,139] | Knock-down enhances morphological differentiation and improves survival [163] | Not specified | Essential for viability and self-renewal of LSCs [175] |
Functional Roles in Immune Cell Differentiation | Plays a role in macrophage differentiation [136] and dendritic cell homeostasis [137] | Ensures immune cell lineage fidelity [131,132,133,134] | Implicated in myeloid development and self-renewal of progenitors [161,162] | Not specified | Influences bone marrow microenvironment interactions [176] |
Contribution to Leukemic Transformation | Potentially oncogenic, may act as a tumor suppressor [129,130] | Involved in myeloid leukemia transformation [135] | Leads to myeloproliferative disorders and AML transformation [162,163] | Promotes leukemogenesis [170] | Promotes disease initiation and maintenance [175] |
Potential Therapeutic Targets | Could offer novel approaches for AML treatment if targeted [146,147,148] | Inhibition may improve outcomes [139,140,141,169] | Knockout or inhibition improves survival [163] | Targeting could impair LSC self-renewal and chemoresistance [171] | Targeting TWIST1 could overcome chemoresistance and influence treatment [178] |
Factor | Survival | Motility | Adherence |
---|---|---|---|
SDF-1 | [207] | [208] | |
METTL-3 | [213] | ||
Integrin β | [188] | [188] | |
N-WASP | [193] | ||
Tks4, Tks5 | [194,195] | ||
E-selectin | [202] | [202] |
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Cuevas, D.; Amigo, R.; Agurto, A.; Heredia, A.A.; Guzmán, C.; Recabal-Beyer, A.; González-Pecchi, V.; Caprile, T.; Haigh, J.J.; Farkas, C. The Role of Epithelial-to-Mesenchymal Transition Transcription Factors (EMT-TFs) in Acute Myeloid Leukemia Progression. Biomedicines 2024, 12, 1915. https://doi.org/10.3390/biomedicines12081915
Cuevas D, Amigo R, Agurto A, Heredia AA, Guzmán C, Recabal-Beyer A, González-Pecchi V, Caprile T, Haigh JJ, Farkas C. The Role of Epithelial-to-Mesenchymal Transition Transcription Factors (EMT-TFs) in Acute Myeloid Leukemia Progression. Biomedicines. 2024; 12(8):1915. https://doi.org/10.3390/biomedicines12081915
Chicago/Turabian StyleCuevas, Diego, Roberto Amigo, Adolfo Agurto, Adan Andreu Heredia, Catherine Guzmán, Antonia Recabal-Beyer, Valentina González-Pecchi, Teresa Caprile, Jody J. Haigh, and Carlos Farkas. 2024. "The Role of Epithelial-to-Mesenchymal Transition Transcription Factors (EMT-TFs) in Acute Myeloid Leukemia Progression" Biomedicines 12, no. 8: 1915. https://doi.org/10.3390/biomedicines12081915