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Review

Epigallocatechin Gallate as a Targeted Therapeutic Strategy Against the JAK2V617F Mutation: New Perspectives for the Treatment of Myeloproliferative Neoplasms and Acute Myeloid Leukemia

by
Leidivan Sousa Da Cunha
1,†,
Isabelle Magalhães Farias
1,†,
Beatriz Maria Dias Nogueira
1,
Caio Bezerra Machado
1,
Flávia Melo Cunha De Pinho Pessoa
1,
Deivide De Sousa Oliveira
1,2,
Guilherme Passos de Morais
1,
André Pontes Thé
1,3,
Patrícia Maria Pontes Thé
4,
Manoel Odorico De Moraes Filho
1,
Maria Elisabete Amaral De Moraes
1 and
Caroline Aquino Moreira-Nunes
1,3,5,*
1
Clinical Genetics Laboratory, Drug Research and Development Center (NPDM), Department of Medicine, Federal University of Ceará, Fortaleza 60020-181, Brazil
2
Departament of Hematology, Fortaleza General Hospital (HGF), Fortaleza 60155-290, Brazil
3
Clementino Fraga Group, Central Unity, Genomics and Molecular Biology Laboratory, Fortaleza 90619-900, Brazil
4
Department of Pharmacy, Federal University of Ceará, Fortaleza 60020-181, Brazil
5
Brazilian Institute of Intelligence in Health, Research and Education, IBISPE, Fortaleza 60160-230, Brazil
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Int. J. Transl. Med. 2025, 5(3), 43; https://doi.org/10.3390/ijtm5030043
Submission received: 21 July 2025 / Revised: 27 August 2025 / Accepted: 9 September 2025 / Published: 15 September 2025
Browse Figures
Versions Notes

Abstract

The JAK2V617F mutation is a major molecular factor in Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) and has been increasingly associated with clonal progression to acute myeloid leukemia (AML), resulting in a poorer prognosis and resistance to conventional therapies. This study integrates a comprehensive literature review with bioinformatic approaches to investigate the potential inhibitory activity of Epigallocatechin Gallate (EGCG), a green tea polyphenol widely recognized for its antioxidant and anticancer properties, on the JAK2V617F mutation. Clinical data from case reports demonstrated heterogeneity in disease progression and frequent therapeutic failures. Molecular docking analysis using the Janus Kinase 2 (JAK2) protein structure (PDB ID: 6D2I) identified a high-affinity binding pocket for EGCG near the V617F mutation site. EGCG exhibited strong binding affinity (−9.2 kcal/mol), forming key interactions with residues Lys581, Ile559, and Leu680, suggesting allosteric modulation of the JH2 pseudokinase domain. To validate our docking protocol, redocking of the known inhibitor AT9283 yielded a favorable Root Mean Square Deviation (RMSD) 2.683 Å and binding energy (−8.3 kcal/mol), confirming the reliability of our approach. Notably, EGCG demonstrated superior binding affinity compared to AT9283 and targets a distinct allosteric site, highlighting its unique mechanism of action and potential as a selective allosteric inhibitor. These findings position EGCG as a promising candidate for future preclinical evaluation, offering a novel strategy to overcome therapy resistance in JAK2V617F-driven malignancies.

1. Introduction

Myeloproliferative neoplasms (MPNs) are a group of chronic hematologic malignancies characterized by the clonal, deregulated proliferation of myeloid lineages in the bone marrow. This leads to the overproduction of mature blood cells. MPNs are classified into three main types: Polycythemia Vera (PV), Essential Thrombocythemia (ET), and Primary Myelofibrosis (PMF), each possessing distinct clinical and molecular features [1,2].
Although they are distinct diseases, they share important phenotypic similarities, such as increased risk of thrombotic events and a tendency to progress to secondary myelofibrosis or acute myeloid leukemia (AML) [1,2,3,4]. Furthermore, MPNs are characterized by recurrent mutations in the JAK2, CALR, and MPL genes. These mutations drive the aberrant and persistent activation of the JAK–STAT signaling pathway, which modulates proliferation, survival, and cellular differentiation [5,6].
The Janus Kinase–Signal Transducers and Activators of Transcription (JAK–STAT) pathway is a signaling cascade involved in crucial cellular mechanisms such as differentiation, metabolism, proliferation, cell survival, and immune response modulation. Its core components are the JAK complexes, a family of tyrosine kinase proteins associated with membrane receptors, and the STATs, a family of transcription activators that transduce signals from the extracellular environment to the nucleus [7,8,9]. Activation occurs through the binding of cytokines and growth factors to specific receptors, which recruit JAKs that subsequently phosphorylate tyrosine residues on STATs, enabling the formation of active dimers that translocate to the nucleus and bind DNA to regulate the gene transcription of various functional targets [10,11].
The JAK2 protein consists of seven homologous domains (JH1 to JH7), each with specific and essential functions for its biological activity. The JH1 domain is responsible for the protein’s catalytic activity, acting as the functional kinase. In contrast, the JH2 domain (pseudokinase) acts as an intramolecular negative regulator of JH1, controlling its activation under physiological conditions. The JH3 and JH4 domains contribute significantly to the protein’s structural stability and participate in the three-dimensional conformation that enables proper interaction between JH1 and JH2, ensuring a balance between activity and inhibition. Finally, the JH5 to JH7 domains include the critical FERM domain, which is essential for anchoring JAK2 to cytokine receptors on the cell membrane. This anchoring allows the transduction of extracellular signals to the intracellular environment, triggering specific cellular responses [12,13,14].
Previous studies have analyzed the frequency and clinical impact of mutations in the JAK2 gene in patients with MPNs, highlighting the high prevalence of the JAK2V617F mutation, particularly in PV, where it occurs in up to 90% of cases, and in ET, in approximately 70%. This mutation is also present in a significant proportion of PMF cases [15,16,17]. The JAK2V617F mutation is a somatic gain-of-function mutation located in the JH2 pseudokinase domain that leads to constitutive activation of the JAK–STAT pathway, promoting cell proliferation independent of external stimuli. For this reason, it constitutes a characteristic and widely used marker in the diagnosis of myeloproliferative disorders [15,16,17].
This mutation occurs in the JH2 domain, substituting valine for phenylalanine at position 617. It promotes π–π interactions between phenylalanines 617 and 595, stabilizing an active conformation of JAK2 and resulting in sustained constitutive activation [12,13]. Patients with a high JAK2V617F allelic burden tend to present more aggressive clinical features, significant leukocytosis, splenomegaly, and a higher risk of disease progression to myelofibrosis or AML. Other mutations are more commonly observed in JAK2V617F-negative patients. These findings reinforce the diagnostic and prognostic relevance of the JAK2V617F mutation, which is associated with unfavorable clinical parameters and an increased risk of progression to AML [18,19,20,21,22].
Dysregulation of this signaling pathway has been widely implicated in the development of various diseases, including hematologic cancers, making it a key factor in tumor progression by directly affecting essential cell cycle processes such as proliferation, survival, and apoptosis [23,24]. Consequently, a variety of drugs have been developed to specifically target the JAK–STAT pathway, aiming to block its abnormal activation. These medications are classified as follows: JAK inhibitors, such as ruxolitinib and tofacitinib; STAT inhibitors, for example, baricitinib; and antibody–cytokine conjugates, which promote a more targeted action on the tumor microenvironment [25,26,27].
Among the most studied alterations in this pathway, the JAK2V617F point mutation stands out as a primary and pivotal genetic driver in the onset and progression of MPNs. Its presence is also related to clonal progression to AML, thereby worsening the patient’s prognosis and complicating clinical management. Moreover, although JAK–STAT pathway inhibitors, such as ruxolitinib, are widely used in current clinical practice, reports of therapeutic resistance, partial response, and relapse have become increasingly frequent, highlighting the urgent need for new, more effective, selective, and durable therapeutic strategies [1,23,24,28].

Epigallocatechin Gallate

Epigallocatechin Gallate (EGCG) is a polyphenol found in green tea (Camellia sinensis), widely recognized for its numerous health benefits. Among its pharmacological properties, antioxidant, antimicrobial, anti-obesity, and anti-inflammatory activities stand out, in addition to its potential in cardiovascular care and brain health, which has drawn growing interest from the scientific community [29,30,31].
Chemically, EGCG is the ester of gallic acid with epigallocatechin, and it features a structure composed of four phenolic rings with multiple hydroxyl groups. This structural conformation allows electron donation and neutralization of free radicals, providing strong antioxidant activity. Its molecular formula is C22H18O11, and its molecular weight is 458 g/mol. Additionally, EGCG is notable for its intrinsic ability to chelate metal ions such as Fe2+ and Cu2+, which contributes to its protective effects against oxidative damage [29,30,32].
Despite its broad spectrum of benefits, the clinical application of EGCG faces significant limitations, mainly due to its low physicochemical stability and reduced oral bioavailability. However, strategies such as EGCG encapsulation in nanoparticles have been explored to overcome these barriers, promoting greater stability, therapeutic efficacy, and a more favorable pharmacokinetic profile [31,33]. Moreover, EGCG has shown potential as a therapeutic agent in the treatment of various types of cancer. The compound exhibits antiproliferative, pro-apoptotic, and anti-angiogenic effects by acting on multiple cellular signaling pathways, thereby enhancing its potential as a target molecule in oncological strategies [33,34,35].
Considering the therapeutic potential of EGCG, including its antioxidant and inhibitory properties across various known cellular pathways, this study aims to evaluate its capacity to modulate the activity of the JAK2V617F mutant protein associated with MPNs. To this end, we will investigate the influence of this mutation in onco-hematological neoplasms and utilize structural bioinformatics tools to perform a thorough analysis of its three-dimensional conformation and dynamics. Based on this analysis, a preliminary rational screening of EGCG as a potential inhibitory agent of the JAK2V617F mutation will be performed. This strategy aims to support the development of innovative therapeutic approaches for the prevention of leukemic transformation and provide additional support for the treatment of patients with MPNs, especially given the challenges related to resistance to conventional JAK–STAT pathway inhibitors.

2. Literature Review and Bioinformatics Analysis Approach

2.1. Selection of Clinical Case Reports

To understand the pathophysiology and severity of the JAK2V617F mutation in patients with MPNs and AML, a literature search was conducted using the PubMed, Scielo, Lilacs, and Embase databases. The keywords used were as follows: “Acute Myeloid Leukemia”, “myeloproliferative neoplasms”, and “JAK2V617F”, combined with the Boolean operator AND. Initially, 59 articles published in the last 10 years were identified. The inclusion criteria were clinical studies involving patients who progressed from an MPN to AML or presented both conditions concomitantly. Literature reviews, preclinical studies, studies without full-text availability, and duplicate articles were excluded.As a result, the number of studies was reduced to 11. This limited sample size reflects the stringent eligibility criteria applied to ensure specificity and clinical relevance to the studied context. All eligible studies are included in Table 1.
In this study, the analyzed articles revealed significant clinical heterogeneity among patients with the JAK2V617F mutation. In addition to the classical subtypes of myeloproliferative neoplasms (MPNs), cases of de novo acute myeloid leukemia (AML) and secondary AML arising from MPN transformation were identified. Frequent co-mutations were observed, including IDH2, SRSF2, TP53, and NPM1, as well as rearrangements involving the RUNX1 and MYC genes. Rare clonal transformations were also noted, such as the acquisition of the BCR::ABL1 e6a2 transcript, associated with Philadelphia-positive AML [36,37,38,39,40,41,42,43,44,45].
Although not all patients displayed complex cytogenetics, this feature was linked to particularly poor outcomes when present. Therapeutic approaches varied and included azacitidine combined with ruxolitinib as first-line therapy, intensive regimens such as 3 + 7 or FLAG-IDA, and IDH2 inhibitors in specific contexts. Most patients died within a year after the AML diagnosis, and approximately 64% experienced relapse or treatment resistance. These findings reinforce the aggressive nature and clonal instability of AML associated with the JAK2V617F mutation, even in the face of modern therapeutic strategies [36,37,38,39,40,41,42,43,44,45].

2.2. Pocket Analysis and Molecular Docking

In this context, beyond discussing the clinical relevance of the JAK2V617F mutation in MPNs and AML, this work proposed a structural approach focused on the mutated protein. Using bioinformatics tools, the binding pockets of JAK2V617F were analyzed with the aim of identifying regions of interest for interaction with a natural-origin inhibitor. This analysis aimed to assess the compound’s potential as a complementary therapeutic candidate, particularly for patients harboring this mutation in aggressive or treatment-refractory disease settings.
Beyond discussing the clinical relevance of the JAK2V617F mutation in MPNs and AML, this work proposed a structural approach focused on the mutated protein. Using bioinformatics tools, the 28 binding pockets of JAK2V617F were analyzed with the aim of identifying regions of interest for interaction with a natural-origin inhibitor. This analysis aimed to assess the compound’s potential as a complementary therapeutic candidate, particularly for patients harboring this mutation in aggressive or treatment-refractory disease settings.
The three-dimensional structure of the protein (PDB ID: 6D2I) was obtained from the Protein Data Bank (PDB) [46]. Structure preparation was conducted using AutoDockTools 1.5.7 [47] and PyMOL 3.0 [48], including the removal of water molecules, addition of polar hydrogens, assignment of Gasteiger charges, and exclusion of the original ligand.
Using the P2Rank tool in PrankWeb [49], two main binding pockets were identified, with particular emphasis on a pocket located near residue 617, directly associated with the V617F mutation. This pocket involves regions between the regulatory JH2 and catalytic JH1 domains, as illustrated in Figure 1A, and showed high accessibility and volume scores, indicating its potential as a target site for docking studies with natural inhibitors. The analysis results are summarized in Table 2, reinforcing the therapeutic viability of strategies targeting the JAK2V617F mutation.
Due to its potent effects for cancer treatment, Epigallocatechin Gallate (EGCG) was selected as the ligand for the docking step, whose structure was retrieved from the PubChem database (CID 65064) [50]. The molecule’s conformation was optimized based on minimum energy. All molecular structures were visualized and analyzed using PyMOL 3.0 [48].
Molecular docking was performed using grid parameters centered on the previously identified pocket 1, ensuring precision in defining the active site for ligand interaction. To guarantee a more comprehensive and detailed conformational sampling of the possible ligand poses, the exhaustiveness parameter was set to 100, significantly increasing the thoroughness of the conformational search and improving overall docking reliability. After docking execution with AutoDock Vina [51], a strong binding affinity was observed, as evidenced by a binding energy value of –9.2 kcal/mol, indicating high stability of the formed complex. Subsequent analyses conducted using Discovery Studio software (version 2025) [52] showed that the ligand was firmly and stably anchored in the catalytic pocket of JAK2V617F (Figure 1B), forming a specific hydrogen bond with the Lys581 residue, in addition to establishing relevant hydrophobic interactions with the Ile559 residue (Figure 2), which is known for its importance in regulating enzymatic activity. Additional residues such as Thr555, Thr557, Ser633, and Leu680 further reinforced the effective occupation of pocket 1, contributing to complex stability and validating the careful selection of the docking grid, highlighting the functional and structural importance of this region as a potential therapeutic target for the selective inhibition of the JAK2V617F mutation.
The ligand’s positioning near the V617F mutation suggests promising potential for specific modulation of the mutated kinase activity, justifying further complementary analyses such as affinity studies and molecular dynamics simulations [47,51]. Additionally, to validate our docking protocol and address reviewer suggestions, we performed a redocking of the known inhibitor AT9283 (co-crystallized in PDB 6D2I), obtaining an RMSD of 2.683 Å and a binding energy of –8.3 kcal/mol. These results were included in the manuscript to allow a direct comparison with EGCG, confirming that while EGCG binds at an allosteric site distinct from AT9283, both compounds exhibit significant binding affinity and inhibitory potential against JAK2, highlighting the unique modulatory role of EGCG [46].

3. Discussion

The JAK2V617F mutation is frequently observed in the early stages of myeloproliferative neoplasms (MPNs) and is considered the most prevalent and significant driver mutation, being essential for diagnosis according to the World Health Organization (WHO) criteria since 2008 [53]. Progression of patients with MPN and the JAK2V617F mutation to acute myeloid leukemia (AML) generally requires the progressive accumulation of additional mutations or complex genetic rearrangements. Recent studies have identified specific chromosomal rearrangements, such as t(8;21)(q22;q22) RUNX1::RUNX1T1 and RUNX1::CBFA2T2, directly associated with the JAK2 mutation [36,40]. Although these translocations are typically favorable markers, their coexistence with the JAK2 mutation is rare and may indicate a poorer prognosis for affected patients [40,54,55]. Furthermore, the JAK2V617F mutation in AML may represent a distinct clinical entity, with its own molecular characteristics and clearly defined unfavorable prognosis [20].
Other variants of the JAK2 gene, besides the V617F mutation, have also been associated with a significantly increased risk of transformation to acute myeloid leukemia (AML), especially the N1108S variant, which is common in secondary AML cases, suggesting greater aggressiveness and worse disease prognosis [56,57]. Beyond its classical and well-established role in myeloproliferative neoplasms (MPNs), the JAK2V617F mutation has been extensively investigated for its possible influence in other hematologic and non-hematologic neoplasms, including various solid tumors. Case reports documented here include patients diagnosed with MPNs and AML who subsequently developed pulmonary adenocarcinoma, diffuse large B-cell lymphoma, and pancreatic adenocarcinoma [44,45]. However, other studies indicate that in situations involving multiple neoplasms, the JAK2V617F mutation reflects the presence of separate hematologic clonality and does not directly influence the development or progression of solid tumors [57,58,59].
Additionally, our detailed results indicate that most patients were treated with the drugs ruxolitinib, azacitidine, and hydroxyurea, which is fully consistent with current clinical guidelines. Ruxolitinib is highlighted as the primary and most effective therapeutic option for the majority of myelofibrosis (MF) cases, while azacitidine is specifically reserved for patients with high-risk features or those in the leukemic transformation phase. Hydroxyurea is widely used to control clinical manifestations and complications associated with polycythemia vera (PV) and essential thrombocythemia (ET) [60,61]. Despite its proven efficacy in hematologic control, the observational data presented in this table indicate that hydroxyurea does not significantly reduce JAK2V617F-mutated clones. The mutation persisted in several patients even after prolonged use of the drug, and progression to AML occurred, demonstrating its overall cytoreductive effect but without specific selective action on mutated cells, as previously described in the scientific literature [62].
Furthermore, significant therapeutic failure was observed even with modern and advanced regimens, such as the combination of azacitidine and ruxolitinib, or the use of Cytarabine combined with Venetoclax and Enasidenib, drugs commonly employed in patients harboring specific epigenetic or metabolic mutations. Although the data from the present study do not allow establishing a direct causal relationship between the JAK2V617F mutation and treatment resistance, the findings point to a relevant and consistent association with unfavorable clinical outcomes and poorer prognosis, as previously reported in several studies in the literature [63,64,65].
In this context, the promising potential use of Epigallocatechin Gallate (EGCG) as a specific allosteric inhibitor of the JAK2V617F mutation in myeloproliferative neoplasms (MPNs) stands out. Scientific studies have already indicated that EGCG can modulate several important cellular signaling pathways, such as the JAK2/STAT3/AKT and p38-MAPK/JNK pathways, which play crucial roles in the development and progression of leukemias associated with JAK2 mutations [66]. This molecular modulation favors increased apoptosis and differentiation of leukemic cells, contributing to disease control. Moreover, EGCG is widely known to inhibit the NFκB pathway, which is frequently hyperactivated in myeloid neoplasms, thus contributing to reduced chronic inflammation and increased cellular apoptosis [67].
Despite the high binding affinity of EGCG with the JH2 domain of JAK2V617F demonstrated in our results, its broad spectrum of biological activity raises concerns about potential off-target effects [29,33]. The promiscuous nature of EGCG may lead to the modulation of multiple non-target signaling pathways, contributing to adverse effects such as hepatotoxicity and drug interactions via inhibition of cytochrome P450 [30,32]. Therefore, the observed antiproliferative effects may involve both the inhibition of JAK2V617F and parallel off-target mechanisms. Strategies such as developing more selective analogs or nanotechnological delivery systems [31] are necessary to maximize therapeutic specificity and minimize side effects.
In our detailed analyses, after performing molecular docking, a stable hydrogen bond formation was observed between EGCG and the LYS581 residue of JAK2V617F, indicating that the ligand fits properly and with high affinity in the specific binding site, thus suggesting good stability of the interaction—a common and desirable characteristic in effective and promising drugs [68,69]. This molecular interaction also reinforces the potential of the LYS581 residue as a strong and crucial anchoring point in this pharmacological interaction.
Additionally, important hydrophobic interactions with the ILE559 residue proved highly relevant. This residue has been previously reported to be directly involved in binding selective JAK2 inhibitors and is located in the pseudokinase domain (JH2). This domain was formerly considered inactive but is now recognized for its fundamental regulatory role in JAK2 activity [70,71]. In this context, it is proposed that the interaction of bioactive compounds with specific allosteric regions, such as the JH2 domain, may represent an effective and promising therapeutic strategy for selective inhibition of JAK2 enzymatic activity.
Furthermore, involvement of residues LEU680, LYS677, THR555, THR557, GLY554, and SER633 suggests that the ligand is situated in a region close to or even overlapping the pseudokinase JH2 domain [70]. This observation further supports the proposal that therapeutic targeting of the JAK2 pseudokinase domain may be a highly promising and effective approach, considering its important role as a negative regulator of kinase activity and the fact that mutations located in this region, such as the V617F mutation, are directly implicated in the pathogenesis and progression of myeloproliferative neoplasms [70,71]. Recent studies reinforce this view, showing that ATP binding to JH2 is critical for pathogenic activation and that alternative targeting strategies in JAK2 may help overcome resistance to conventional inhibitors [28,72].

4. Conclusions

Our results reinforce the relevance of the JAK2V617F mutation not only as a diagnostic marker in MPNs but also as a potentially implicated factor in the progression to AML and in therapeutic resistance. The persistence of this mutation even after treatment with cytoreductive and hypomethylating agents highlights the need for more specific approaches. In this context, the results of the molecular docking demonstrated that Epigallocatechin Gallate (EGCG) has a strong binding affinity with the JAK2V617F protein, interacting with key residues of the JH2 pseudokinase domain, a critical region for the regulation of this kinase’s activity. These observations suggest that EGCG could act as a promising allosteric inhibitor, with the potential to selectively modulate the mutated form of JAK2. Therefore, further studies are essential to validate and expand the current findings. Approaches such as molecular dynamics simulations, in vitro assays using MPN and AML cell lines harboring the JAK2V617F mutation, and preclinical studies will allow a deeper understanding of EGCG’s efficacy and feasibility as a targeted therapeutic agent. These studies could assess effects on cell viability, apoptosis, and JAK–STAT pathway modulation, while supporting the development of formulations that overcome the compound’s limitations. In the long term, these results will provide experimental support for the in silico findings and establish a solid foundation for therapeutic applications. Rational targeting of the JH2 domain remains a promising strategy to personalize onco-hematological therapy in patients with MPNs and AML associated with the JAK2V617F mutation.

Author Contributions

Invitation received, C.A.M.-N.; conceptualization, L.S.D.C., I.M.F. and C.A.M.-N.; provision of data and sub-sequent analysis and interpretation, L.S.D.C., I.M.F., B.M.D.N., F.M.C.D.P.P., C.B.M., D.D.S.O., G.P.d.M., M.O.D.M.F. and M.E.A.D.M.; writing—original draft preparation, L.S.D.C., I.M.F. and C.A.M.-N.; writing—review and editing, C.B.M., D.D.S.O., B.M.D.N., F.M.C.D.P.P., A.P.T., P.M.P.T. and C.A.M.-N.; funding acquisition, C.A.M.-N. All authors have read and agreed to the published version of the manuscript.

Funding

This study was supported by Brazilian funding agencies: Coordination for the Improvement of Higher Education Personnel (CAPES) grant number 404213/2021-9, National Council of Technological and Scientific Development (Productivity in Research Scholarships to M.O.D.M.F, and CAM-N), Cearense Foundation of Scientific and Technological Support (FUNCAP) grant number P20-0171-00078.01.00/20.

Conflicts of Interest

The authors declare no conflicts of interest. The funders had no role in the design of the study; in the collection, analyses, or data interpretation; in the writing of the manuscript, or in the decision to publish the results.

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Figure 1. Prediction and visualization of the binding site in the JAK2V617F protein. (A) Surface representation of the protein with binding pockets predicted by the PrankWeb tool. Pocket 1, selected for molecular docking, is highlighted in blue. (B) PyMOL visualization of the complex formed between the JAK2V617F protein (in green) and Epigallocatechin Gallate (EGCG), showing the ligand positioned within the defined pocket.
Figure 1. Prediction and visualization of the binding site in the JAK2V617F protein. (A) Surface representation of the protein with binding pockets predicted by the PrankWeb tool. Pocket 1, selected for molecular docking, is highlighted in blue. (B) PyMOL visualization of the complex formed between the JAK2V617F protein (in green) and Epigallocatechin Gallate (EGCG), showing the ligand positioned within the defined pocket.
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Figure 2. Molecular interactions between Epigallocatechin Gallate (EGCG) and the JAK2V617F protein. On the left, a 2D representation of the ligand’s interactions with key residues in the JH2 domain of the protein, highlighting hydrogen bonds (green lines) and hydrophobic interactions (pink lines). On the right, 3D visualizations in PyMOL and Discovery show the positioning of EGCG within the binding site and its spatial interactions with adjacent residues.
Figure 2. Molecular interactions between Epigallocatechin Gallate (EGCG) and the JAK2V617F protein. On the left, a 2D representation of the ligand’s interactions with key residues in the JH2 domain of the protein, highlighting hydrogen bonds (green lines) and hydrophobic interactions (pink lines). On the right, 3D visualizations in PyMOL and Discovery show the positioning of EGCG within the binding site and its spatial interactions with adjacent residues.
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Table 1. Summary of Clinical Studies Investigating the JAK2V617F Mutation in Patients with Myeloproliferative Neoplasms and Acute Myeloid Leukemia.
Table 1. Summary of Clinical Studies Investigating the JAK2V617F Mutation in Patients with Myeloproliferative Neoplasms and Acute Myeloid Leukemia.
PatientEarly DiagnosisDisease EvolutionInitial
Treatment		Recurrence and New TreatmentClinical OutcomeReference
Woman, 62 years oldDiagnosed with breast cancer and treated with lumpectomy, anastrozole, radiation, and adjuvant chemotherapy.Diagnosed with PMF with JAK2V617F, IDH2, and SRSF2 mutations.Progression to AML with RUNX1::CBFA2T2 rearrangement.
AML with adverse risk classification.		Use of azacitidine + ruxolitinib
Remission for 4 months		Use of Cytarabine + Venetoclax + Enasidenib with modified chemotherapy regimens after relapseDeath 13 months after AML diagnosis.[36]
Woman, 68 years old Diagnosed with MDS with fibrosis MF-2 and JAK2V617F mutation.Progression to AML with 16% initial blasts progressing to high grade.
AML with intermediate risk classification.		Use of hypomethylating agent: 5-azacytidine Death 2 months after MDS diagnosis.[37]
Man, 60 years oldDiagnosed PMF with MF-3 with JAK2V617F mutation.Diagnosed with BPDCN.Progression to AML; with intermediate risk classification.Use of hydroxyurea, splenic irradiation, and ruxolitinib Death 1 month after diagnosis of persistent AML.[37]
Woman, 75 years oldDiagnosed with AML, treated with chemotherapy (7 + 3); 2 high-dose cytarabine consolidation cycles.
AML with intermediate risk classification.		Progression to PV with JAK2V617F mutation (43.4%) and TET2 R550 mutation (46%).After progression to PV: therapeutic phlebotomy + hydroxyurea. Patient under follow-up after progression to PV, 19 months post-consolidation.[38]
Woman, 44 years oldDiagnosed with APL with PML/RARα bcr3 mutation.
APL with adverse risk classification.		Progression to PV and ET with JAK2V617F and TP53 P278R mutations.Use of ATRA + ATO, with daunorubicin and cytarabine for cytoreduction.
Use of dexamethasone for differentiation syndrome; induction followed by 3 consolidation cycles.		Treatment with interferon for MPN (PV/ET) 22 months after complete remission of APL.Patient with stable clinical course under interferon treatment.[39]
Woman, 74 years oldDiagnosed with ET with JAK2V617F mutation. Using hydroxyurea for ET control.Progression to secondary AML with t(8;21)(q22;q22.1); RUNX1::RUNX1T1; JAK2V617F mutation.
AML with favorable risk classification.		Treatment with chemotherapy using venetoclax + azacitidine. Hematologic and molecular remission of AML after chemotherapy, but JAK2V617F mutation still present in peripheral leukocytes.[40]
Girl, 1 year old Diagnosed with AML with 49% blasts, JAK2V617F mutation, and complex karyotype.
AML with adverse risk classification.		Progression to possible underlying ET.Induction 1:
Daunorubicin + cytarabine + etoposide (MRD: 0.37%)
Induction 2:
Idarubicin + cytarabine + etoposide (MRD: 0.52%)		Induction 3:
Mitoxantrone + HiDAC leading to hematologic failure and relapse.		Death 1 month after treatment discontinuation due to AML relapse.[41]
Woman, 64 years oldDiagnosed with AML with 49% blasts, JAK2V617F mutation, and normal karyotype.
AML with intermediate risk classification.		Progression to unclassified MPN with JAKV617F mutation, diagnosed 7 years after AML remission, with initial fibrosis detected.Treatment with daunorubicin + cytarabine (3 + 10), 3 consolidation cycles, and no active therapy after remission. Patient in continuous remission, asymptomatic, and without active treatment.[42]
Man, 34 years oldDiagnosed with gout; chronic pain following a traffic accident; and bipolar disorder.Diagnosed with AML NPM1 and JAK2V617F mutations.
AML with intermediate risk classification.		Progression to transient underlying MPN.Treatment with FLAG-IDA (fludarabine + cytarabine + idarubicin + G-CSF).Allogeneic peripheral blood stem cell transplant after megakaryocytic hyperplasia and JAK2 positivity.Patient in complete remission with no relapse of AML or MPN until the last evaluation.[43]
Man, 68 years oldDiagnosed with multiple cardiovascular comorbidities (hypertension, coronary artery disease, deep vein thrombosis, pulmonary embolism) and pulmonary conditions (COPD, stage IA lung adenocarcinoma).Diagnosed with ET with JAK2V617F mutation.Progression to Chronic Myelomonocytic Leukemia with adverse risk classification
Development of DLBC. Progression to AML-M5 with adverse risk classification.		Use of hydroxyurea for MPN
Use of R-CHOP for DLBCL
Use of chemotherapy (7 + 3) with cytarabine and idarubicin for AML-M5		Use of decitabine, platelet apheresis for thrombocytosis, and allogeneic transplantation.Death following transplant failure, AML relapse, and palliative care.[44]
Man, 80 years oldDiagnosis of type 2 diabetes; atrial fibrillation; cerebrovascular disease; polymyalgia rheumatica; and osteoporosis.Diagnosis of primary myelofibrosis with JAK2V617F mutation.Progression to AML with BCR-ABL1 e6a2 mutation (Ph+) with adverse classification.
Development of pancreatic adenocarcinoma (advanced stage).		Use of hydroxyurea + anagrelide + dasatinib + valproic acid.Doses and schedules adjusted due to toxicity; anagrelide and dasatinib discontinued due to side effects; transition to imatinib with partial response; partial control of AML with TKI.Death weeks after progression to pancreatic cancer[45]
NMP: myeloproliferative neoplasm, AML: acute myeloid leukemia, PV: polycythemia vera, TE: essential thrombocythemia, PMF: primary myelofibrosis, SMD: myelodysplastic syndrome, LPA: acute promyelocytic leukemia, DLBCL: diffuse large B-cell lymphoma, MF: myelofibrosis, DRM: measurable residual disease, BPDN: blastic plasmacytoid dendritic cell neoplasm, DVP: deep vein thrombosis, DAC: coronary artery disease, DPOC: chronic obstructive pulmonary disease.
Table 2. Binding pocket characteristics identified in the JAK2V617F protein using the P2Rank tool (PrankWeb).
Table 2. Binding pocket characteristics identified in the JAK2V617F protein using the P2Rank tool (PrankWeb).
PocketScoreProbabilitySAS PointsSuface AtomsCenter (x, y, z)
Pocket18.430.4968144(−20.25, 8.93, 145.79)
Pocket27.870.4616838(−15.91, 8.93, 157.82)
Legend: Analysis of the binding site characteristics identified in the JAK2V617F protein. The accessibility score, binding probability, number of solvent-accessible surface (SAS) points, number of surface atoms, and the geometric center coordinates of each pocket are presented. Pocket 1, which showed the highest score and number of SAS points, was selected as the target region for molecular docking studies with EGCG.
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Cunha, L.S.D.; Farias, I.M.; Nogueira, B.M.D.; Machado, C.B.; Pessoa, F.M.C.D.P.; Oliveira, D.D.S.; de Morais, G.P.; Thé, A.P.; Thé, P.M.P.; Moraes Filho, M.O.D.; et al. Epigallocatechin Gallate as a Targeted Therapeutic Strategy Against the JAK2V617F Mutation: New Perspectives for the Treatment of Myeloproliferative Neoplasms and Acute Myeloid Leukemia. Int. J. Transl. Med. 2025, 5, 43. https://doi.org/10.3390/ijtm5030043

AMA Style

Cunha LSD, Farias IM, Nogueira BMD, Machado CB, Pessoa FMCDP, Oliveira DDS, de Morais GP, Thé AP, Thé PMP, Moraes Filho MOD, et al. Epigallocatechin Gallate as a Targeted Therapeutic Strategy Against the JAK2V617F Mutation: New Perspectives for the Treatment of Myeloproliferative Neoplasms and Acute Myeloid Leukemia. International Journal of Translational Medicine. 2025; 5(3):43. https://doi.org/10.3390/ijtm5030043

Chicago/Turabian Style

Cunha, Leidivan Sousa Da, Isabelle Magalhães Farias, Beatriz Maria Dias Nogueira, Caio Bezerra Machado, Flávia Melo Cunha De Pinho Pessoa, Deivide De Sousa Oliveira, Guilherme Passos de Morais, André Pontes Thé, Patrícia Maria Pontes Thé, Manoel Odorico De Moraes Filho, and et al. 2025. "Epigallocatechin Gallate as a Targeted Therapeutic Strategy Against the JAK2V617F Mutation: New Perspectives for the Treatment of Myeloproliferative Neoplasms and Acute Myeloid Leukemia" International Journal of Translational Medicine 5, no. 3: 43. https://doi.org/10.3390/ijtm5030043

APA Style

Cunha, L. S. D., Farias, I. M., Nogueira, B. M. D., Machado, C. B., Pessoa, F. M. C. D. P., Oliveira, D. D. S., de Morais, G. P., Thé, A. P., Thé, P. M. P., Moraes Filho, M. O. D., Moraes, M. E. A. D., & Moreira-Nunes, C. A. (2025). Epigallocatechin Gallate as a Targeted Therapeutic Strategy Against the JAK2V617F Mutation: New Perspectives for the Treatment of Myeloproliferative Neoplasms and Acute Myeloid Leukemia. International Journal of Translational Medicine, 5(3), 43. https://doi.org/10.3390/ijtm5030043

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