Role of JAK2 V617F in Myeloproliferative Neoplasms: From Mutation to Manifestation: A Review

Abstract

Myeloproliferative neoplasms (MPNs) are clonal hematopoietic stem cell disorders characterized by excessive production of one or more mature myeloid lineages. The JAK2 V617F point mutation — present in nearly all patients with polycythemia vera (PV) and in approximately 50% of those with essential thrombocythemia (ET) and primary myelofibrosis (PMF) — is the principal molecular driver in Philadelphia chromosome (Ph)-negative MPNs. This review, conducted in accordance with PRISMA 2020 guidelines, aimed to evaluate the clinical manifestations (thrombosis, splenomegaly, and bleeding), hematological parameters, serum lactate dehydrogenase (LDH) levels, and risk of disease progression to acute leukemia or myelofibrosis associated with the JAK2 V617F mutation. A comprehensive literature search was performed across PubMed/MEDLINE, Embase, Scopus, and Web of Science for studies published between 2005 and 2025. Following screening of 1,100 candidate records, 10 primary studies encompassing 3,311 patients were included in the final synthesis. Methodological quality was assessed using the Newcastle-Ottawa Scale (NOS). The included studies demonstrate that the majority of JAK2 V617F-positive MPN patients are older than 50 years, with no marked sex predilection. Splenomegaly and thrombotic events were frequently reported across cohorts. Serum LDH levels, hematocrit, and hemoglobin were consistently elevated, while leukocytosis was the predominant hematological finding, though white blood cell (WBC) counts varied widely across MPN subtypes. A minority of patients demonstrated disease transformation to acute leukemia or myelofibrosis. These findings underscore the central prognostic and diagnostic significance of JAK2 V617F in Ph-negative MPNs and highlight its value in clinical risk stratification and therapeutic monitoring.

Introduction

Background

Myeloproliferative neoplasms (MPNs) represent clonal disorders of the hematopoietic system, defined by the excessive proliferation of myeloid lineages within the bone marrow, a concept first introduced by William Dameshek in 1951.[1] According to the World Health Organization (WHO), MPNs include chronic myeloid leukemia (CML), chronic neutrophilic leukemia (CNL), chronic eosinophilic leukemia (CEL), polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (PMF), juvenile myelomonocytic leukemia (JMML), and MPN, not otherwise specified (NOS).[2] This spectrum is defined by the excessive proliferation of erythroid, megakaryocytic, or granulocytic lineages, frequently complicated by thromboembolic events and progression to acute leukemia; consequently, thrombosis, hemorrhage, and evolution into overt myelofibrosis or acute myeloid leukemia (AML) constitute the principal causes of morbidity and mortality.[3]

Recent advances in molecular diagnostics have transformed clinical practice by enabling the precise detection of critical genetic mutations. Philadelphia chromosome–negative MPNs, comprising PV, ET, and PMF — were fundamentally redefined in 2005 following the discovery of the JAK2 V617F mutation in the majority of affected patients, thereby establishing a shared genetic foundation across this group.[4,5] Mutations in JAK2, most notably the JAK2 V617F point mutation in exon 14, have been identified in a large proportion of Ph-negative MPN patients.[6,7,8,9] These mutations are linked to chronic inflammation, constitutional symptoms, and elevated thrombotic risk.[10] JAK2 V617F represents a gain-of-function mutation in the pseudokinase (JH2) domain, disrupting its inhibitory regulation of the kinase (JH1) domain and thereby driving constitutive kinase activation.[13] This mutation plays a critical role in mediating downstream signaling through multiple cytokine receptors, including the erythropoietin receptor.[11]

Increasing JAK2 V617F mutation burden is directly associated with MPN progression, reflecting a biological continuum ranging from essential thrombocythemia through polycythemia vera to primary myelofibrosis.[12] Evaluation of JAK2 V617F allele burden provides valuable insight into thrombotic risk and disease progression in patients with JAK2 V617F-positive PV and ET.[15] In PMF, however, neither mutational status nor allele burden of JAK2 V617F has been shown to significantly affect overall survival or leukemia-free survival.[16] Current evidence suggests that JAK2 V617F-associated MPN development may be influenced not only by mutant allele burden, but also by diversesignaling pathways, epigenetic modifications, immune system interactions, and lifestyle factors.[17] Patients with a JAK2 V617F allele burden exceeding 75% are considered high-risk, given their increased susceptibility to thrombo-hemorrhagic events throughout disease progression.[18]

Objectives

• 1.To evaluate existing literature assessing the clinical features, including thrombosis, splenomegaly, and bleeding, of JAK2 V617F-positive MPN.
• 2.To analyze correlations between the JAK2 V617F mutation and hematological parameters and serum LDH level.
• 3.To determine the association between the JAK2 V617F mutation and risk of disease progression to myelofibrosis or acute leukemia.

Methods

Protocol and Registration

This review was conducted without prior registration in a recognized registry such as PROSPERO. Protocol registration was not completed prior to the commencement of the review, which represents a limitation. The review methodology, eligibility criteria, and planned analyses were prospectively defined and documented before the literature search was initiated. Future updates of this review will be registered prospectively.

Eligibility Criteria Inclusion Criteria:

• Primary observational studies (cohort, cross-sectional, and case-control designs) written in English

• Studies including adult patients (≥18 years of age) with a confirmed diagnosis of MPN

• Studies including more than 10 patients

• Studies published between 2005 and 2025 (from the year of JAK2 V617F discovery onward)

• Studies reporting quantitative JAK2 V617F allele burden or mutational status with at least one clinical or hematological outcome

Exclusion Criteria:

• Reviews, meta-analyses, narrative reviews, case reports, and editorials

• Studies involving patients younger than 18 years of age

• Studies with fewer than 10 patients

• Studies not reporting JAK2 V617F mutational status

• Studies not written in English

• Studies involving Philadelphia chromosome–positive MPN (i.e., CML)

Population: Adult patients (≥18 years) with a confirmed diagnosis of a Ph-negative MPN (PV, ET, or PMF) or related myeloid neoplasm with JAK2 V617F mutation status reported.

Information Sources and Search Strategy

A literature search was conducted in the following databases: PubMed/MEDLINE, Embase, Scopus, and Web of Science. The search covered the period from January 2005 to April 2025. Google Scholar was used as a supplementary source only; records identified through this route were cross-verified against the primary databases before inclusion. NCBI was not used as a standalone database.

The following search strategy was applied, adapted as required by each database's controlled vocabulary:

("JAK2 V617F" OR "JAK2V617F" OR "Janus kinase 2 mutation") AND ("myeloproliferative neoplasm*" OR "polycythemia vera" OR "essential thrombocythemia" OR "primary myelofibrosis" OR "MPN") AND ("allele burden" OR "mutation burden" OR "thrombosis" OR "splenomegaly" OR "disease progression" OR "leukemia transformation")

MeSH terms used included: Janus Kinase 2/genetics, Myeloproliferative Disorders, Polycythemia Vera, Thrombocythemia Essential, Primary Myelofibrosis, Mutation, Alleles, Thrombosis, Splenomegaly. Boolean operators (AND, OR) were applied throughout. The date of the last search was April 30, 2025.

Study Selection

Two reviewers (O.D. and A.K.D.) independently screened titles and abstracts, followed by full-text evaluation of potentially eligible studies. Disagreements were resolved through discussion; a third reviewer was available for arbitration if consensus could not be reached. Studies were included if they met all pre-specified eligibility criteria.

Data Extraction

O.D. and A.K.D. independently extracted data on: study characteristics (year of publication, country, study design, setting), participant characteristics (number of subjects, median age, sex distribution), JAK2 V617F mutational status and allele burden, clinical features (thrombosis, splenomegaly, bleeding), hematological parameters (hemoglobin, WBC, platelet count, hematocrit), serum LDH level, and disease progression outcomes. Discrepancies were resolved by consensus.

Risk of Bias Assessment

Methodological quality of included studies was assessed using the Newcastle-Ottawa Scale (NOS) for observational studies. Cohort studies were evaluated across three domains: selection of study groups (maximum 4 stars), comparability of groups (maximum 2 stars), and assessment of outcomes (maximum 3 stars), yielding a maximum score of 9 stars. Cross-sectional studies were assessed using the NOS adapted version for this design. Studies with NOS scores of 7–9 were considered low risk of bias; scores of 4–6 indicated moderate risk; scores below 4 indicated high risk of bias. Results are presented in Table 5.

Data Synthesis

Given the substantial clinical and methodological heterogeneity across included studies — including variation in study design, MPN subtypes (PV, ET, PMF, CMML), populations, and outcome definitions — statistical pooling via meta-analysis was not performed. Instead, a narrative synthesis approach was adopted. Results are described descriptively, organized by outcome domain: clinical manifestations, hematological parameters, serum LDH, and disease progression. Where possible, ranges of observed values and between-study variation are noted.

Results

Study Selection

The literature search identified 1,100 candidate records across PubMed/MEDLINE, Embase, Scopus, and Web of Science. After removal of duplicates, 1,062 records were excluded on the basis of title and abstract screening using the pre-specified eligibility criteria. The remaining 38 studies were retrieved for full-text evaluation. Following detailed assessment, 28 studies were excluded at the full-text stage (reasons: systematic reviews or meta-analyses excluded per protocol [n = 7]; insufficient reporting of JAK2 V617F status [n = 8]; sample size fewer than 10 [n = 5]; non-English language [n = 2]; no relevant clinical outcomes reported [n = 6]). A total of 10 primary studies met all inclusion criteria and were included in the final synthesis. Note that two separate publications by MM Khazeem (2025) are included (references [24] and [27]), as these report distinct patient cohorts and different outcome measures. A PRISMA 2020 flow diagram is provided as supplementary material.

Study Characteristics

Table 1 summarizes the characteristics of the 10 included studies, encompassing a total of 3,311 patients from eight countries. Study designs included cohort studies (n = 7), cross-sectional studies (n = 2), and one mixed cross-sectional/cohort design. Median patient age across studies ranged from 54 to 72 years, consistent with the well-established age-related predominance of MPNs. Among the 3,311 patients, 2,758 (83.3%) were confirmed JAK2 V617F-positive.

Table 1.

Characteristics of included studies and patient cohorts.

Author, Year, Ref	Country	Study Type	Selected Population	Median Age, Years (Range)	No. of Patients (F/M)	JAK2 V617 F- Mutated Patients	Thrombotic Events	Splenomegaly	Bleeding
AJ Lee et al, 2021 [15]	South Korea	Retrospective	JAK2 V617F- positive PV and ET	69 (27– 88)	127 (75/52 )	127	51	—	—
Y Zhang et al, 2020 [19]	China	Cohort	JAK2 V617F- mutated MPN	54 (18–89)	1,537 (798/7 39)	1,537	675	925	—
RH Zulkefl eeet al, 2021 [20]	Malay sia	Cross-sectional + Cohort	Diagnosed MPN ≥20 years of age	57.58(44.0 6– 70.7)	159(70/89 )	117	65	69	—
R Singdo ng et al, 2016 [21]	Thaila nd	Cohort	Diagnos ed MPN	66.25 (47–82)	100 (50/50 )	82	26	7	—
L Hu et al, 2016 [22]	China	Cohort	Ph- negativ e MPN	59.06 (NR)	133 (61/72)	84	29	74	—
E Şahin et al, 2021 [23]	Turke y	Cohort	Ph- negativ e MPN	59.87 (41–77)	410 (205/2 05)	298	100	—	43
MM Khazee m, 2025 [24]	Iraq	Cross- sectional	JAK2 V617F- mutated MPN	60 (18– 87)	162 (71/91)	162	—	—	—
MM Patnaik et al, 2019 [25]	USA	Cohort	JAK2 V617F- positive CMML	72 (61– 85)	30 (9/21)	30	2	13	—
MM Khazee m et al, 2025 [27]	Iraq	Cohort	JAK2 V617F- positive MPN	63.03 (58.17– 67.43 )	37 (20/17)	37	12	—	—
G Barosi et al, 2007 [30]	Italy	Cohort	JAK2 V617F- positive PMF	56 (45– 64)	86 (31/55)	86	12	31	—

Hematological Parameters

Hematological data from seven studies are summarized in Table 2. Hemoglobin levels were generally elevated in PV and ET patients but were lower in PMF cohorts (median Hb as low as 9.40 g/dL in PMF). WBC counts showed considerable variability across studies and subtypes, ranging from leukocytopenic values to marked leukocytosis (up to 131 × 10³/μL in a CMML cohort). Platelet counts were elevated in ET and related cohorts. Hematocrit was above the normal threshold in the majority of PV-inclusive studies.

Table 2.

Hematological parameters of JAK2 V617F-positive MPN patients.

Author, Year, Ref	Country	Study Type	Selected Population	No. of Patients (F/M)	JAK2 V617F- Mutated Patients	Hb (g/dL), WBC (×103/μL), Platelet (×103/μL) — Median (Range)	Haematocrit % (Range)
RH Zulkeflee et al, 2021 [20]	Malaysia	Cross- sectional + Cohort	Diagnosed MPN ≥20 years of age	159 (70/89)	117	Hb: 14.34 (8.03– 20.4) WBC: 18.69 (8.49– 36.9) Platelet: 162 (16– 840)	45.08 (25.85– 65.84)
MM Khazeem, 2025 [24]	Iraq	Cross- sectional	JAK2 V617F- mutated MPN	162 (71/91)	162	Hb: 15.35 (5.3–23.1) WBC: 13.45	49.7 (12.1– 72.1)(3.0–64.4) Platelet: 473.5 (7.9– 2,484)
MM Patnaik et al, 2019 [25]	USA	Cohort	JAK2 V617F- positive CMML	30 (9/21)	30	Hb: 12.1 (7.2–16.9) WBC: 15.7 (4.1– 131) Platelet: 162 (16– 840)	37 (23–55)
M Aksit et al, 2020 [26]	Turkey	Cohort	MPN (Ph- negative)	168 (86/82)	94	Hb: 14.8 (11.1– 18.5) WBC: 11.2 (1.4– 112.4) Platelet: 626.8 (311.6– 942)	45.1 (35.8– 54.4)
MM Khazeem et al, 2025 [27]	Iraq	Cohort	JAK2 V617F- positive MPN	37 (20/17)	37	Hb: 13.61 (9.37– 17.47) WBC: 14.51 (5.4– 25.16) Platelet: 636.3 (331.8– 1,218)	42.77 (29.08– 56.18)
M Arif et al, 2024 [28]	Pakistan	Cohort	JAK2 V617F- positive PMF	21 (NR)	21	Hb: 9.40 (7.75– 11.05) WBC: 11.03 (5.4– 25.53) Platelet: 234 (16– 591.3)	—
G Barosi et al, 2007 [30]	Italy	Cohort	JAK2 V617F- positive PMF	86 (31/55)	86	Hb: 13 (11–14.7) WBC: 9.38 (6.8– 13.8) Platelet: 354 (203– 653)	—

Serum LDH and Bleeding Manifestations

Serum LDH and bleeding data from five studies are presented in Table 3. Serum LDH was elevated above the upper limit of normal in all reporting cohorts. The highest median LDH values were observed in PMF cohorts (953.7 U/L in Arif et al., 2024; 730 U/L in Barosi et al., 2007), consistent with the greater degree of ineffective hematopoiesis and extramedullary erythropoiesis in this subtype. Bleeding events were infrequently reported across included studies; Şahin et al. (2021) documented bleeding in 43 of 298 JAK2 V617F-mutated Ph-negative MPN patients.

Table 3.

Serum LDH levels and bleeding manifestations in JAK2 V617F-positive MPN patients.

Author, Year, Ref	Country	Study Type	Selected Population	No. of Patients (F/M)	JAK2 V617F- Mutated Patients	Bleeding Manifestation (n)	Serum LDH — Average, U/L (Range)
RH Zulkeflee et al, 2021 [20]	Malaysia	Cross- sectional + Cohort	Diagnosed MPN ≥20 years of age	159 (70/89)	117	—	842.93 (335.3– 4,145)
E Şahin et al, 2021 [23]	Turkey	Cohort	Ph- negative MPN	410 (205/205)	298	43	367.1 (155– 595)
MM Patnaik et al, 2019 [25]	USA	Cohort	JAK2 V617F- positive CMML	30 (9/21)	30	—	378 (137– 971)
M Arif et al, 2024 [28]	Pakistan	Cohort	JAK2 V617F- positive PMF	21 (NR)	21	—	953.7 (657.1– 1,250.3)
G Barosi et al, 2007 [30]	Italy	Cohort	JAK2 V617F- positive PMF	86 (31/55)	86	—	730 (469– 1,045)

Disease Progression to Leukaemia and Fibrosis

Data regarding progression to leukemia or myelofibrosis are summarized in Table 4. Across four reporting studies, leukemic transformation was documented in a minority of patients: 4/184 (2.2%) in Hindilerden et al. (2014), 9/298 (3.0%) in Şahin et al. (2021), and 47/86 (54.7%) in Barosi et al. (2007) — the latter representing a PMF-specific cohort in which transformation risk is inherently higher. Progression to myelofibrosis was documented in 12/30 (40%) of JAK2 V617F-positive CMML patients (Patnaik et al., 2019).

Table 4.

Progression to leukaemia and myelofibrosis in JAK2 V617F-positive MPN patients.

Author, Year, Ref	Country	Study Type	Selected Population	No. of Patients (F/M)	JAK2 V617F - Mutated Patients	Progressi on to Leukaemia (n)	Progressi on to PMF/BM Fibrosis (n)	Follow-up
IY Hindilerd en et al, 2014 [16]	Turkey	Coho rt	JAK2 V617F- positive Ph-negative MPN	184 (101/83)	184	4	—	NR
E Şahin et al, 2021 [23]	Turkey	Coho rt	Ph- negative MPN	410 (149/261)	298	9	—	NR
MM Patnaik et al, 2019 [25]	USA	Coho rt	JAK2 V617F- positive CMML	30 (9/21)	30	—	12	NR
G Barosi et al, 2007 [30]	Italy	Coho rt	JAK2 V617F- positive PMF	86 (31/55)	86	47	—	NR

Risk of Bias Assessment

Table 5 presents the NOS-based quality assessment of all 10 included studies. NOS scores ranged from 5 to 8 out of 9. Eight studies were rated as low to moderate risk of bias (NOS ≥6). One study (Khazeem et al., 2025 [27]) received a score of 5, reflecting limited comparability data and incomplete outcome reporting. The 2007 cohort by Barosi et al., while methodologically sound, reflects an earlier diagnostic era and may not align fully with current WHO MPN classification criteria.

Table 5.

Newcastle-Ottawa Scale (NOS) risk of bias assessment.

Author, Year	Country	Study Design	Selection (max 4 stars)	Comparability (max 2 stars)	Outcome (max 3 stars)	Total NOS Score (max 9)
AJ Lee et al, 2021	South Korea	Retrospective cohort	★★★	★★	★★★	8
Y Zhang et al, 2020	China	Cohort	★★★	★★	★★	7
RH Zulkeflee et al, 2021	Malaysia	Cross- sectional/Cohort	★★★	★	★★	6
R Singdong et al, 2016	Thailand	Cohort	★★★	★	★★	6
L Hu et al, 2016	China	Cohort	★★★	★★	★★	7
E Şahin et al, 2021	Turkey	Cohort	★★★	★★	★★★	8
MM Khazeem, 2025 [24]	Iraq	Cross-sectional	★★★	★	★★	6
MM Patnaik et al, 2019	USA	Cohort	★★★	★★	★★★	8
MM Khazeem et al, 2025 [27]	Iraq	Cohort	★★	★	★★	5
G Barosi et al, 2007	Italy	Cohort	★★★	★★	★★★	8

Discussion

This review examined the association between JAK2 V617F mutation and a range of clinical, hematological, and prognostic outcomes in patients with Ph-negative MPNs. The findings, synthesized from 10 primary studies encompassing 3,311 patients across eight countries, confirm the central role of JAK2 V617F as both a diagnostic marker and a clinical determinant in PV, ET, and PMF.

Age and Sex Distribution

Across all included studies, the majority of JAK2 V617F-positive MPN patients were older than 50 years, consistent with the age-related accumulation of somatic mutations and the well-documented demographic profile of MPN. JAK2 V617F positivity was identified in patients as young as 18 years, though prevalence rises markedly with age, reflecting clonal hematopoiesis dynamics.[24] Regarding sex, no strong or consistent sex-based differences in JAK2 V617F positivity rates were identified across studies. One cohort reported that women were diagnosed at a younger age and had lower median WBC counts and JAK2 V617F allele burdens than men; paradoxically, vascular event rates were at least equivalent between sexes.[29] This observation underscores the importance of evaluating sex as a modifier of clinical risk in future prospective studies.

Splenomegaly and Thrombosis

Splenomegaly was a frequent finding in JAK2 V617F-positive patients, driven by extramedullary hematopoiesis secondary to abnormal cytokine signaling. The strongest data come from Zhang et al. (2020), in which 925 of 1,537 patients reported splenomegaly, illustrating the burden of this complication at scale. Thrombotic events — both arterial and venous — were consistently associated with JAK2 V617F positivity. The mutation approximately doubles the risk of thrombosis in ET patients, while its contribution in PMF remains less clearly defined.[31] In the large Chinese cohort by Zhang et al. (2020), thrombosis occurred in 675 patients (43.9%), underscoring the magnitude of this risk. Allele burden appears to modulate this risk further: patients with a burden exceeding 75% are at substantially higher risk of thrombo-hemorrhagic complications.[18] Clinical features such as WBC count, hemoglobin, splenomegaly, and thrombosis show significant correlations with JAK2 V617F allele burden, particularly in PV.[32]

Hematological Parameters and LDH

Hemoglobin, hematocrit, and WBC levels varied considerably by MPN subtype. PV-predominant or inclusive cohorts consistently demonstrated elevated hemoglobin and hematocrit, whereas PMF cohorts showed lower hemoglobin levels (median as low as 9.40 g/dL), consistent with the marrow fibrosis impairing effective erythropoiesis. Platelet counts were elevated in ET-inclusive cohorts, with some studies reporting values exceeding 600 × 10³/μL. WBC counts ranged from leukocytopenia to marked leukocytosis, reflecting the heterogeneous biology of MPNs. ET patients harboring JAK2 V617F demonstrated a phenotype resembling PV, characterized by elevated hemoglobin, hematocrit, and serum LDH, alongside higher rates of thrombosis.[35] Serum LDH was consistently elevated across all reporting cohorts and was highest in PMF, corroborating its role as a marker of disease activity and tumor burden.[12]

Disease Progression

Disease transformation to leukemia or myelofibrosis occurred in a subset of patients across included studies, though transformation rates varied considerably by MPN subtype. In PMF cohorts — where transformation risk is inherently higher — Barosi et al. (2007) documented leukemic transformation in 54.7% of cases. Rates in PV and ET cohorts were substantially lower (approximately 2–3%), consistent with existing literature on the natural history of these entities. JAK2 V617F mutational status predicted progression to large splenomegaly and leukemic transformation in PMF.[30] In contrast, in PMF, the allele burden alone has not been shown to independently predict overall survival or leukemia-free survival.[16]

Limitations of Included Studies

Several limitations of the primary studies must be acknowledged. First, there was significant heterogeneity in study design (cross-sectional versus cohort), patient populations (single MPN subtype versus mixed), and outcome definitions across studies. Second, follow-up duration was not consistently reported, limiting the assessment of long-term outcomes. Third, the majority of studies did not include a mutation-negative comparator group, precluding direct comparison of outcomes by JAK2 V617F status. Fourth, some studies predated the WHO 2016 and 2022 revised diagnostic criteria, meaning patient classification may not be fully consistent across included cohorts. Fifth, allele burden quantification methods varied (e.g., allele-specific PCR versus next-generation sequencing), introducing potential measurement heterogeneity.

Limitations of This Review

This review has several inherent limitations. The review was not prospectively registered in PROSPERO or any equivalent registry, which limits reproducibility and transparency. A formal meta-analysis was not performed due to substantial clinical and methodological heterogeneity, meaning effect estimates could not be quantitatively pooled. The search strategy, while comprehensive, did not include grey literature, conference abstracts, or non-English publications, potentially introducing publication bias. Furthermore, only 10 studies met the final inclusion criteria for tabulation, and the overall sample is geographically skewed toward Asian and Middle Eastern populations, which may limit generalizability. Finally, the use of narrative synthesis without a formal synthesis framework (such as the Synthesis Without Meta-Analysis [SWiM] framework) represents a methodological gap that should be addressed in future iterations.

Clinical Implications

These findings have several implications for clinical practice. JAK2 V617F allele burden monitoring can guide risk stratification in patients with PV and ET, informing decisions regarding cytoreductive therapy and anticoagulation. Patients with high allele burden (>75%) warrant intensified monitoring and potentially more aggressive thromboprophylaxis. The consistent elevation of serum LDH across MPN subtypes supports its use as a routine biomarker of disease activity and treatment response. Awareness of sex-related differences in vascular risk — particularly the apparently equivalent or heightened risk in women despite lower allele burdens — should inform personalized risk-benefit discussions.

Future Research Directions

Future prospective, multi-center studies with standardized allele burden measurement and outcome definitions are needed to better characterize the prognostic value of JAK2 V617F in individual MPN subtypes. Specifically, subgroup analyses stratified by PV, ET, and PMF should be prioritized to disentangle subtype-specific effects. Long-term follow-up data addressing the relationship between allele burden trajectory and transformation risk are lacking. Additionally, integration of JAK2 V617F status with emerging molecular markers (CALR, MPL, ASXL1) in multivariable prognostic models represents an important research frontier. Formal protocol registration, comprehensive search strategies, and validated risk-of-bias assessment should be standard practice in future systematic reviews in this field.

Conclusion

JAK2 V617F positivity is predominantly observed in patients older than 50 years, independent of sex, and is consistently associated with splenomegaly, thrombotic events, elevated serum LDH, and altered hematological parameters across PV, ET, and PMF. Disease transformation to leukemia or myelofibrosis, while occurring in a minority of unselected patients, is substantially more common in PMF cohorts. The strong correlation between JAK2 V617F allele burden and disease phenotype underscores its diagnostic, prognostic, and therapeutic monitoring value in Ph-negative MPNs. Standardized prospective studies and rigorous systematic review methodology will be essential to fully characterize the clinical significance of this mutation across the full MPN spectrum.