Amar Yeware- School of Medicine and Public Health (SMPH), Department of Medicine, University of Wisconsin-Madison, Madison, WI, United States
The acquired JAK2V617F mutation is predominantly detected in hematopoietic stem cells(HSCs), leading to myeloproliferative neoplasms(MPN). Emerging evidence shows that JAK2V617F bearing cells remodel their microenvironment by dysregulating cytokines, and altering adhesion molecules, with histopathological changes in the spleen and liver that influence thrombosis and disease progression. However, how JAK2V617F bearing cells interact with and modify niche factors to promote MPN progression remains insufficiently defined and represents an important therapeutic opportunity. This review focuses on the effect of mutant HSCs on the BM niche, emphasizing key signaling pathways such as IL-β1, TPO/MPL, TGF-β1, VEGF, CXCR4/CXCL12, and altered metabolism. Understanding these dysregulated interactions provides a rationale for therapies that directly target the niche components. Current therapies, including JAK inhibitors, partially address symptoms but are limited by resistance and off-target effects, whereas emerging niche-directed strategies such as such as CXCR4 antagonists, TGF-β1 blockers and metabolic modulators, may restore normal hematopoiesis and overcome ruxolitinib resistance. Therefore, understanding and modulating these HSC-niche interactions advances a path toward durable and transformative therapies for MPNs.
Background: myeloproliferative neoplasm disease and niche
Myeloproliferative neoplasms (MPNs) are a group of disorders characterized by uncontrolled expansion of hematopoietic stem cells (HSCs), including erythroid, megakaryocytic (MK), and granulocytic lineages (1). The World Health Organization (WHO) classifies MPNs into several categories, including polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (PMF), chronic myeloid leukemia (CML), chronic neutrophilic leukemia, chronic eosinophilic leukemia, and unclassifiable MPN (MPN-U) (2). Among these, MPNs with the JAK2V617F mutation commonly found in PV, ET, and PMF display distinct clinical and pathological features and carry variable risks of thrombosis, marrow fibrosis, leukemic transformation, or progression to secondary acute myeloid leukemia (AML) (3). These observations highlight how JAK2V617F alterations in HSCs contribute to disease heterogeneity and clinical outcomes, emphasizing the functional impact of the bone marrow (BM) microenvironment on disease progression.
Approximately 50-60% of patients with ET or PMF carry the JAK2V617F mutation, while an additional 5-10% harbor mutations in the myeloproliferative leukemia gene (MPL). MPL functions as the receptor for thrombopoietin (TPO) and signals through the JAK2 pathway in HSCs, suggesting that MPL mutations may share consequences similar to JAK2V617F in MPN. However, clinical observations indicate that MPL mutant patients do not exhibit altered rates of thrombosis, hemorrhage, transformation, or death compared with JAK2V617F-positive patients (4). MPL mutations are also detected at lower frequency (5-10%) in ET and PMF (3) suggesting that they may arise later and play a relatively minor role in disease development. Some ET or PMF patients lack both JAK2V617F and MPL mutations but instead carry somatic calreticulin (CALR) mutations (5, 6), although co-occurrence of CALR with JAK2V617F has been reported in a small fraction of MPN cases (1-6.8%) (7, 8). CALR mutations activate central JAK-STAT signaling and can drive MPN, but they are associated with younger age and higher platelet counts and have also been reported in occasional BCR-ABL positive CML cases, limiting their specificity (3, 9). A small subset of patients remain negative for JAK2V617F, MPL, and CALR (2% of PV and 10-15% of PMF and ET), yet most MPN cases involve JAK2V617F or other alterations affecting common JAK-STAT signaling (10). Notably, the JAK2V617F mutation is detected in 75% of ET and 97% of PV patients at diagnosis, demonstrating the importance of precise and sensitive assessment of JAK-STAT pathways in MPN (11). Together, these mutations represent a common denominator in MPN through hyperactive JAK/STAT signaling and highlight gaps in understanding how these alterations interact and influence the BM microenvironment.
HSCs generate over 100 billion blood cells daily. The BM is a highly organized tissue that provides a niche supporting HSC differentiation, proliferation, and self-renewal (12). Most HSCs remain quiescent (1-8% of the total), constituting long term repopulating HSCs (LT-HSCs). Physiological changes or genetic alterations can increase HSCs/HSPCs proliferation and mobilization of mature blood cells or platelets into circulation. Activation of LT-HSCs depends on cytokines and growth factors produced by niche cells within the BM microenvironment, including stromal cells, endosteal cells, Schwann cells, endothelial cells, and even distant tissues such as the liver and lung (13). These factors similarly influence proliferation of pathogenic JAK2V617F bearing HSCs and contribute to disease progression (14). Therefore, this review focuses on how JAK2V617F mutant HSCs expand and differentiate into disease phenotypes while benefiting from supportive microenvironmental niche factors. Additionally, treatment strategies that target both JAK2 signaling and BM microenvironmental pathways are discussed.
Origin of JAK2V617F mutant bearing cells in MPN and lineage skewness in to either PV or ET phenotype
The JAK2V617F mutation commonly arises in HSCs and is subsequently detected in downstream progenitors, including MK, erythroid, myeloid, and lymphoid lineages. However, the mechanisms underlying the increased self-renewal capacity of JAK2V617F-mutant HSCs compared with healthy HSCs and the selective bias toward erythroid or MK differentiation in MPN subtypes remain unpredictable (15). Some of this lineage skewing in PV and ET has been attributed to alterations in interferon-pSTAT1 signaling. Specifically, reduced pSTAT1 activity in erythroid progenitors contributes to PV development, whereas elevated pSTAT1 in MKs is associated with ET disease progression (16). Notably, Grockowiak et al. (2023) reported that activation of CDC42, a small Rho-GTPase, is increased in PV but negatively correlates with ET and within their corresponding HSC populations (17). This altered CDC42 polarity is regulated by pSTAT1 dependent mechanisms downstream of aberrant JAK2V617F signaling. The authors further demonstrated that CDC42 driven polarity disrupts the spatial distribution of HSCs in the bone marrow, reshaping their microenvironment in distinct ways such as sinusoidal dilation in PV and expansion of the endosteal niche in ET. Together, these findings suggest that intrinsic signaling differences driven by JAK2V617F mutant HSCs alter their interactions with specific bone marrow niches, contributing to the divergent phenotypes of PV and ET. Nevertheless, it remains unclear whether this lineage bias arises solely from HSC intrinsic JAK2V617F alterations or is further shaped by lineage specific reprogramming and niche derived signals. These aspects are explored below using cell specific JAK2V617F mutation models.
JAK2V617F in erythroid and MK cells drives distinct outcomes in MPNs
For erythroid skewness, Dupont S et al. (2007) identified two subsets of PV patients based on the clonal genotypic pattern of the JAK2V617F mutation: (1) homozygous JAK2V617F mutant erythroid progenitors that do not require erythropoietin (EPO) for terminal proliferation, and (2) heterozygous JAK2V617F mutant erythroid progenitors that require EPO for terminal proliferation (18). Additionally, erythroid lineage restricted heterozygous JAK2V617F expression in EpoR-Cre mice resulted in a mild form of MPN, whereas homozygous JAK2V617F expression in EpoR-Cre mice caused a severe form of MPN, with greater erythroid colony growth observed even in the absence of EPO (19). These findings suggest that homozygous JAK2V617F mutation in erythroid cells can lead to a more severe PV phenotype than the heterozygous form and that lineage restricted expression of JAK2V617F is sufficient to promote MPN development. Moreover, when myeloid or lymphoid progenitors from MxCre; JAK2wt/VF mice or erythroid progenitors from EpoR-Cre-JAK2VF/VF mice HSCs were transplanted into healthy recipients, MPN symptoms were not detected over a 16-week period, indicating that these progenitors cannot regulate HSC self-renewal in secondary recipients which could develop disease (19). In contrast, MK-lineage-restricted PF4-Cre mice expressing transgenic human JAK2V617F in MK cells developed a clear MPN phenotype and expansion of HSCs (20, 21). Furthermore, an increased number of HSC/HSPCs (E-SLAM cells) was observed in both PF4-Cre-JAK2V617F mice and in recipient mice transplanted with JAK2V617F bearing MKs, indicating that transgenic JAK2V617F bearing MKs can modulate HSC self-renewal and proliferation to drive MPN progression (20, 21). Although transgenic model systems may involve non physiologic expression, and a report also suggested that PF4-Cre mice carrying heterozygous JAK2V617F in MKs develop MPN features by secreting IL-6 and promoting aberrant erythropoiesis (22). Woods B et al. (2019) also emphasized that JAK2V617F mutant MKs can promote neoplastic growth of JAK2 wild type cells in a cell non autonomous manner, and ablation of heterozygous JAK2V617F mutant MKs significantly reduces disease burden, supporting the hypothesis that MK restricted JAK2V617F mutation can drive HSC expansion and development of MPN (22). However, Mansier O et al. (2019) challenged this possibility, reporting that PF4-Cre driven JAK2V617F expression may be leaky in HSCs, and therefore that clonal expansion of HSCs underlies MPN pathogenesis in this model instead of MK restricted JAK2V617F expression (23) It should be noted that erythroid and MK cells are the ultimate terminal progeny of JAK2V617F mutant HSCs; therefore, lineage restricted JAK2V617F progenitor cells are becoming essential for MPN progression. Additionally, these terminal progenitors can function as a niche by secreting various cytokines, such as IL-6 or TGF- β1 from JAK2V617F MKs.
JAK2V617F neutrophils drives thrombocytosis or MPN like progression
In the context of JAK2V617F specific neutrophils, Haage TR et al. (2024) showed that Ly6G-Cre based expression of JAK2V617F, but not CALR mutations, promoted thrombosis progressions (24). The authors also reported that JAK2V617F neutrophils exhibited increased production of inflammatory cytokines, such as IL-1α, IL-2, and M-CSF, which leads to MK hyperplasia in the BM and subsequent thrombocytosis. Another study observed ‘emperipolesis of neutrophils within MKs’ in approximately 84% of MPN patient samples, suggesting that pathogenic neutrophils can transfer their contents to platelets, potentially driving thrombotic progression beyond the typical emperipolesis process (25). Moreover, JAK2V617F neutrophils are resistant to apoptosis, and their abnormal JAK2-STAT5 signaling upregulates the “don’t eat me” signal (CD24hi) on neutrophils. This CD24 upregulation allows them to evade efferocytosis and invade into MK cells, thereby contributing to thrombocytosis disease progression that can be abrogated by CD24 deletion or anti-CD24 blockade (26). Taken together, these findings support that JAK2V617F neutrophils, as niche cells, are sufficient to induce the MPN phenotype independent of HSC specific mutations, through increased inflammatory cytokine production and emperipolesis.
JAK2V617F bearing endothelial cells in MPN development
Apart from hematopoietic progenitors, evidence suggests that JAK2V617F mutations in niche cells of HSCs can contribute to MPN development. For example, the occurrence of JAK2V617F in ECs of the hepatic vein has been reported in Budd-Chiari Syndrome (BCS), where severe thrombotic events resemble those seen in PV (27). However, not all BCS patients harbor JAK2V617F mutations, suggesting that the mutation may be localized to specific tissues where PV-like symptoms appear. Similarly, the spleen, a site of extramedullary hematopoiesis, has been shown to harbor JAK2V617F mutant ECs in myelofibrosis patients, supporting the idea that localized JAK2V617F bearing ECs can contribute to MPN development (28). Specifically it was observed that JAK2V617F ECs enhance the growth of JAK2V617F mutant HSCs at in vitro co-culture compared to wild type HSCs (29) and transplantation of JAK2V617F HSCs into JAK2V617F EC mice results in greater HSC expansion than in wild type EC recipients (30). Authors also highlight that there is an upregulation of the CXCL12 and SCF in the JAK2V617F ECs which are major contributor of HSCs expansion and self-renewal activity. In addition, human pluripotent stem cell derived JAK2V617F ECs and PDGF-b-Cre mice carrying JAK2V617F ECs exhibits enhanced pro-thrombotic and adhesive phenotype compared to wild type ECs (31, 32), implying that as perivascular niche JAK2V617F ECs could be major contributors to thrombosis during MPN progression. However, previous studies used Tie2-Cre-based ECs specific JAK2V617F recipients, it should be noted that Tie2 is also expressed in other niche cells, such as fibroblasts and osteoclast precursors; therefore, contributions from these resident cells could influence MPN like progression. Additionally, ECs specific JAK2V617F (Cdh5-Cre-JAK2Wt/V617F mice) mutation was not sufficient alone to induce substantial HSC expansion or full MPN like disease, except only mild thrombocytosis (33). Therefore, these outcomes underscore that JAK2V617F mutant ECs alone may not be sufficient to drive MPN progression, highlighting the need to consider interactions with other niche cells and HSCs.
Normal hematopoietic niche
The niche of HSCs is complex and transitions through a series of stages from embryonic development to the adult stage (13). Primarily, HSCs niche transition occurs from the embryonic sac at the primitive stage, then shifts to the fetal liver with time, and finally resides in the complex and organized mature BM, which serves as the site for storage, self-renewal, and differentiation of HSCs. At present, the BM vasculature is broadly identified as a network of thin walled, fenestrated sinusoidal endothelial cells and smooth muscle invested arterioles (34). However, the BM microenvironment further comprises a variety of niche cells that collectively regulate HSC maintenance, proliferation, and lineage fate decisions. The major niche cells that influence HSC frequency and function are described below.
Osteoblasts cells
These cells are derived from multipotent mesenchymal stromal cells (MSCs), and are the predominant cell type along with the endosteum in BM. They are primary bone forming cells and lined at the edge of bone, certainly called endosteal. Earlier, it was considered that osteoblasts produce CXCL12 or other chemokines to support HSCs activity, but use of advanced microscopy and genetic tools found that they contribute less to HSCs maintenance (13). Nevertheless, osteoblasts produce several cytokines or have specific ligand binding interactions with HSCs (e.g., Notch ligand) and are described as a major component in the construction of fibrosis in PMF patients (35).
Stromal cells
These are the second most abundant cell types present in BM and are considered primary regulators of HSCs, as they produce CXCL12, transforming growth factor-β1 (TGF-β1), stem cell factor (SCF), and activate growth signaling pathways such as Notch and WNT. A variety of stromal cell subtypes are present in BM, including Nestin+ cells, NG cells, CXCL12-abundant reticular (CAR) cells, and leptin receptor positive (LEPR+) cells. Importantly, Nestin+ cells exist at both arteriolar and sinusoidal regions and maintain the quiescence of HSCs during early developmental stages (especially near the arteriole site) (36). Likewise, LEPR+ and CAR cells are predominantly found in the sinusoidal region, where they overlay the ECs layer and regulate HSCs through secretion of CXCL12 and SCF in the adult stage (37, 38).
Endothelial cells
The ECs are specifically lined along the sinusoidal and arteriolar blood vessels and constitute approximately 0.01-0.03% of total BM cells (38). A distinct characteristic of ECs in BM tissue is that they are tightly organized around arterioles, whereas sinusoidal vasculature is comparatively more permeable (39). ECs express several adhesion molecules on their surface, such as VCAM, C-CAM, and P-selectin, and serve as a major site for SCF production within the splenic microenvironment. Moreover, Hooper et al. (2009) showed that conditional mutation or inhibition of vascular endothelial growth factor receptor 2 (VEGFR2) prevents sinusoidal EC regeneration and HSC reconstitution (34), indicating that sinusoidal ECs play a fundamental role in HSC homing and engraftment in BM.
Neural cells
Schwann cells, along with neurons or sympathetic nerve fibers, are rarely found in BM tissue, primarily localized near arteriolar sites. Although their major functions are not directly associated with HSCs, they regulate stromal cells to facilitate HSC engraftment through synaptic signaling and are also responsible for activating latent TGF-β1 within the BM microenvironment (40).
Monocytes/macrophages and regulatory T cells
These cells are distributed throughout BM, accounting for approximately 0.4-1% of total cells, and their primary function is to stimulate immune responses against antigens. It is suggested that macrophages induce HSC proliferation and mobilization by secreting granulocyte colony-stimulating factor (G-CSF), which disrupts the CXCL12-CXCR4 interaction (41). Meanwhile, regulatory T cells produce IL-6, which promotes HSC self-renewal and regulates HSPC function (13).
HSCs progenitors
The most abundant progenitors found in BM are multipotent HSCs, including granulocyte-monocyte blasts and erythroid-megakaryocyte blasts. Among these, MKs are particularly important as niche cells, as they are physically associated with HSCs in the BM and their ablation leads to the activation of quiescent HSCs and an increase in their proliferation (42). Furthermore, authors have shown that MKs can transiently dominate TGF-β1 mediated inhibitory signaling to stimulate HSC expansion. In addition, MKs are commonly located near the sinusoidal regions and produce fibroblast growth factor 1 (FGF1), which recognized for promoting the proliferation and mobilization of HSPCs (43). Moreover, Hazlewood et al. (2023) reported that PF4-SRSF3 knockout mice exhibited reduced platelet production and increased BM HSC mobilization and EMH (44), suggesting that highly polyploid large cytoplasmic megakaryocytes (LCM) act as negative regulators of HSC activity and are critical for platelet formation. Taking together, these findings highlight MKs as key niche components that regulate HSC maintenance and proliferation, either through direct cell contact and LCM morphology or by secreting cytokines such as TGF-β1 and FGF1. Besides MKs, macrophages and other regulatory cells, such as Treg cells, also contribute to HSC maintenance, primarily through inflammation dependent mechanisms.
Oncogenic HSCs derived cytokines and BM niche remodeling in MPN progression
It is well known that oncogenic HSCs can alter the function of MSCs, vasculature, and other BM resident cells by secreting specific cytokines, thereby promoting disease progression. For example, sympathetic nerve fibers, Schwann cells, and Nestin+ MSCs are consistently reduced in the bone marrow of MPN patients or in mice carrying the human JAK2V617F gene in HSCs (45). The reduction of these cells is mediated by HSC derived interleukin-1β (IL-1β), particularly which disrupts the interaction between sympathetic nerve fibers and the β3-adrenergic receptor on Schwann cells or Nestin+ MSCs, triggering MSC loss in BM. Furthermore, the loss of MSCs decreases CXCL12 levels in BM, resulting in enhanced HSC proliferation and disease progression. The authors further demonstrated that IL-1β mediated effects on MSCs can be halted by addition of a β3-adrenergic receptor agonist, which restores MSC numbers and limits MPN progression by reducing HSC proliferation (45), indicating that nerve cells indirectly affect HSC proliferation via MSC reduction, while oncogenic HSCs cytokines such as IL-1β that alter their niche cells.
In another microscopic study of normal BM tissue, Gli+ MSCs were predominantly localized near the endosteum (68.1 ± 2.7%) and a smaller fraction (31.9 ± 2.7%) near the perivascular niche. While in bone marrow fibrosis, this distribution shifts and higher fraction of Gli+ MSCs increasing in the perivascular region (46). Moreover, oncogenic hematopoietic progenitors, such as MKs, produce CXCL4 chemokines, which drive Gli+ MSC differentiation into myofibroblasts that contribute to the origin of PMF (46, 47). Altogether, these findings suggest that oncogenic HSCs/HSPCs or their niche secrete cytokines and factors that remodel the BM microenvironment, promoting MPN development. These factors are reviewed individually below with their correlation to MPN progression and summarized in Table 1 and Figure 1.
Table 1. HSCs niche factors and their implication in MPN phenotype.
Figure 1. Schematic illustrating how JAK2V617F drives polycythemia vera (PV) or polycythemia vera (ET), remolds niche components and drug targeting of niche factor interactions. Changes in STAT1 signaling and CDC42 level drives polarity shifts that contribute to PV or ET disease. Various niche cells produce cytokines that act on HSCs (green arrows), while HSCs derived factors (red arrows) influencing MPN disease progression. Drugs targeting these cytokine-niche interactions are numbered as follows: 1. Ruxolitinib; Momelotinib, 2. Sotatercept; Fresolimumab, 3. β-aminopropionitrile; PXS-LOX-1/2, 4. MDX-1338;Plerixafor, 5. PX-478; Echinomycin, 6. BPTES, 7. PRM-151 (PTX-2), highlighting potential strategies to restore normal HSC function.
Disrupted CXCL12/CXCR4 signaling and shift of HSC BM to splenic niches in MPNs
The discovery of highly purified HSCs as CD150+CD48-CD41- cells enabled detailed analysis of hematopoietic cell localization using multicolored antibodies and advanced microscopy techniques. These studies confirmed that most HSCs reside adjacent to sinusoidal blood vessels, i.e., in the perivascular niche of the BM and spleen (48–50). The perivascular area primarily consists of an EC layer overlaid by stromal CAR cells, creating a niche abundant in the chemokine CXCL12, which binds to the CXCR4 receptor on HSCs (37). Importantly, receptor CXCR4 is highly expressed in self-renewing HSCs, particularly those in close contact with CAR cells, compared to their progenitors. Genetic ablation or inhibition of CXCR4 in HSCs leads to: a) decreased HSC self-renewal, b) altered cell intrinsic interactions in transplanted mice, and c) increased HSPC numbers (37, 51), indicating that CXCR4/CXCL12 aberrant signaling results in HSC expansion in the BM.
MF or myeloid metaplasia patients, HSCs from display significantly reduced CXCR4 expression, although no statistical association with JAK2V617F mutational status was observed (52), links the CXCR4-CXCL12 signaling to MPN disease progressions. Interestingly, Wang X et al. (2015) reported elevated levels of both intact and truncated CXCL12 in the splenic plasma of MF patients, which promoted migration of HSC/HSPCs toward the spleen, and was reduced in the presence of anti-CXCL12 neutralizing antibodies (53). This suggests that CXCL12 acts as a chemoattractant in the spleen, potentially facilitating EMH and MPN progression. Conversely, peripheral blood (PB) and BM plasma from PV or PMF patients contain decreased levels of intact CXCL12 but show an increase in truncated CXCL12 forms (54). Thus, it suggest that the truncated or inactive form of CXCL12 may be critical during MPN progression.
Similarly, JAK2V617F-ECs exhibited increase of CXCL12 mRNA expression and also support MPN progression (30, 55), which raises the possibility that CXCL12 may exert pleiotropic effects in the JAK2V617F BM microenvironment or much of it may be translated into inactive or truncated proteins in the BM, whereas functional CXCL12 persists in the spleen, possibly promoting EMH. Overall, the CXCL12/CXCR4 signaling axis plays a critical role in maintaining the dynamic relationship between HSCs and the BM or EMH microenvironments, which is crucial for MPN disease development. Further studies are needed to reconcile the discrepancy between CXCL12 mRNA and truncated protein activity in JAK2V617F mutant microenvironments.
SCF signaling and its contribution to MPN pathogenesis
SCF is a growth factor produced by ECs or LEPR+ stromal cells within the vascular niche of HSCs, as demonstrated using SCF-GFP knock in mice. Deletion of SCF results in a reduced HSC frequency in the BM (38), suggest that SCF is critical for the HSCs proliferation. The increased SCF mRNA expression was observed in the JAK2V617F bearing ECs of Tie2-Cre mice, indicating that elevated SCF levels are essential for HSC expansion and MPN development (30). Additionally, SCF binding affinity and internalization were higher in PV patient erythroid progenitors compared with normal erythroid progenitors, accompanied by a marked increase in Akt/PKB phosphorylation (56, 57). These observations suggest that elevated SCF can drive excessive proliferation of erythroid progenitors in PV via activation of the central Akt/PKB pathway.
TGF-β1: a dual regulator of HSC maintenance and myelofibrosis development
The quiescence maintaining factor TGF-β1 is produced by multiple cells in the BM, including MKs, monocytes, and vascular niche cells such as Schwann cells (40, 42). TGF-β1 production is regulated by FGF1through autocrine feedback in MKs; for example, increased FGF1 production reduces TGF-β1 levels, thus it is making the TGF-β1-FGF1 balance crucial for HSC proliferation (42, 43). In MPN disease, upregulation of FGF1 was observed in JAK2V617F-bearing MKs of PF4-Cre mice, whereas TGF-β1 levels remained unaffected (20, 21). In addition, patients with myelofibrosis or myeloid metaplasia exhibit increased levels of PDGF and TGF-β1 (58) suggesting a distinct role for TGF-β1 in MPN phenotypes compared with normal hematopoiesis. TGF-β1 is also a potent inducer of fibrosis via myofibroblasts, making it a critical contributor to PMF pathophysiology.
Yao JC et al. (2019) transplanted JAK2V617F mutant HSCs into mice lacking the TGF-β receptor in MSCs and observed reduced fibrosis, while hematopoiesis remained intact. This indicates that TGF-β1 signaling is essential for MSC mediated myelofibrosis but does not affect JAK2V617F HSC expansion (59). Furthermore, authors showed transplantation of JAK2V617F HSCs with TGF-β receptors double mutations into wild-type mice did not result in clonal expansion, suggesting that JAK2V617F mutated HSCs are TGF-β1 dependent for clonal expansion in MPN development (59). In their recent study, the authors showed that genetic ablation of TGF-β1 signaling in MSCs, but not osteo lineage cells, prevents the development of myelofibrosis (60). This process is mediated by noncanonical c-Jun N-terminal kinase (JNK) signaling, and treatment of mice with a JNK inhibitor similarly prevents myelofibrosis. Interestingly, the authors also documented that loss of TGF-β1 signaling in MSCs does not restore the impaired hematopoietic niche function in MPNs, as evidenced by persistent decreases in bone marrow cellularity, HSC/HSPC numbers, and expression of CXCL12 and Kitlg, along with the development of EMH. Taken together, these findings suggest that TGF-β1 is essential for MPN progression, particularly for myelofibrosis development, while it does not regulate the impaired niche or clonal hematopoiesis.
TPO–MPL Axis: critical for HSC expansion and MPN development
Although activation of MPL mutation in hematopoietic cells has been reported in the development of ET and PMF in a small number of patients, the MPL receptor plays a central role in HSC cycling through TPO signaling (3). TPO is a long range factor secreted mainly by the liver and kidney, primarily regulating MK proliferation and differentiation to control circulating platelet numbers (13). In particular, platelets from PV patients exposed to TPO exhibited impaired protein tyrosine phosphorylation compared with healthy platelets (61), indicating that TPO signaling is impaired in the context of JAK2V617F mutation. Furthermore, MPL-/- mice showed fail of restoration of JAK2V617F HSC/HSPC expansion compared to WT MPL mice (62), suggesting that MPL is necessary for MPN phenotype development. Although, JAK2V617 HSCs and TPO-/- double knockout mice exhibited mild splenomegaly and reduced thrombocythemia compared with WT mice, but transplantation of JAK2V617F marrow into TPO null mice failed to induce MPN phenotype, confirming the essential role of TPO in MPN development (62). Conversely, JAK2V617F bearing ECs also show increased MPL expression, while MPL mutant ECs display reduced SCF and CXCL12 levels (29, 30), suggesting that enhanced TPO-MPL signaling in JAK2V617F ECs may promote HSC expansion via increased CXCL12 or SCF secretion and contributing to MPN progression. However, this observation is contradicted by previous studies used MPL null mice or the current report of EC specific JAK2V617F / MPL-/- knockout mice (33), indicating that endothelial MPL does not significantly contribute to HSC/HSPC expansion or MPN like disease development. Therefore, the role of the MPL-TPO axis appears to be primarily restricted to HSCs/HSPCs in MPN development.
Role of VEGF in HSC expansion and microenvironment remodeling in MPNs
An internal autocrine loop of VEGF is essential for HSC expansion, as observed in vitro and in transplanted mice when VEGF function was ablated by mutation or inhibited using small molecules in HSCs (63). Similarly, increased microvascular density and elevated serum VEGF levels have been identified in MPN patients (64, 65). Moreover, markedly increased VEGF levels have been reported in several case studies of MPN patients (66–68) as well as in vitro co-culture of ECs (29) and it is speculated that this VEGF increase facilitates new vessel formation during high allelic burden of JAK2V617F. In addition, ruxolitinib, an inhibitor of JAK2, subsequently reduces VEGF expression in HEL cell culture, indicating that VEGF is produced by hematopoietic cells and that enhanced angiogenesis is directly related to JAK2V617F mutation burden (69). However, Butler JM et al. (2010) demonstrated an indirect regulatory association between VEGF and HSC expansion, whereby VEGF secreted by hematopoietic cells causes translocation of the Jagged-2 ligand to the EC surface; this translocation subsequently promotes regeneration and expansion of HSCs (70). Therefore, increased VEGF in JAK2V617F HSCs may not only drive angiogenesis but also support HSC self-renewal by modulating the microenvironment and cell surface interactions.
Context-dependent roles of Notch signaling in MPN
The Jagged-2 cytokine is a member of the Notch signaling pathway and is also present on BM stromal cells, ECs, and osteoblasts, where it promotes HSC regeneration after myeloablation. Importantly, alterations in Notch signaling have been reported to modify arteriole numbers as well as SCF production in the extracellular matrix, which could directly affect HSC expansion (13, 71). However, the direct role of Notch signaling in JAK2V617F mutant HSC expansion and MPN development has not yet been reported. Alternatively, Mind bomb-1 (Mib1), an essential component for Notch ligand function, has been studied in Mib1 knockout mice, which develop a de novo MPN phenotype after wild type BM transplantation (72), demonstrating that defective Notch ligand signaling could also be important for MPN phenotype development. Nevertheless, some reports suggest that Notch signaling supports T cell differentiation and proliferation, while it can impair early B cell differentiation in acute lymphoid leukemia (ALL) and chronic lymphoid leukemia (CLL) (73, 74). Additionally, human subject studies suggest a tumor suppressive role of Notch signaling, whereas murine studies indicate a potential oncogenic role, highlighting the context dependent and sometimes contradictory function of Notch signaling in hematopoietic malignancies.
Histopathological changes in the HSC niche during MPN progression
BM and PB histology remain key diagnostic and classification tools for MPNs. Alterations in HSC/HSPC numbers or their localization within the BM niche are characteristic features of MPN progression. For example, erythroid and myeloid hyperplasia are prominent in PV but absent in ET and PMF. In compare, ET patients show markedly increased MK size with staghorn (hyper-lobulated) nuclei in the BM and the presence of giant platelets in the PB. While PMF patients exhibit enlarged MKs with bulbous nuclear morphology arranged in tight clusters within the BM region (75). Likewise, in JAK2V617F mutant PF4-Cre mice, MK numbers were increased and were detected in closer contact with sinusoidal regions compared with normal MKs (76), suggesting that disease specific difference in cellular appearance. Remarkably, retrovirally transduced JAK2V617F donor BM cells in Balb/C mice exhibited splenomegaly and diffuse reticulin fibrosis in BM which is comparatively low or none in C57Bl/6 mice (77), suggesting a strain specific difference in histopathological presentation. Collectively, these findings indicate that JAK2V617F mutation not only alters marrow histology but also exhibits variation in pathological appearances depending on cell type and strain specific context. Such differences may provide valuable insights for differentiating MPN subtypes and understanding disease progression.
Increased vascular density and VEGF expression are evident in MPNs; however, sinusoidal dilation within the BM lumen becomes particularly prominent during MK expansion and platelet differentiation events (78). Although ECs are the major component of the sinusoid and their altered function has been well established in MPN development, it remains unclear whether sinusoidal permeability is directly modified in response to JAK2V617F mutation. Interestingly, increased vascular leakiness and reduced rigidity of blood vessels were reported in recipient mice transplanted with AML patient derived HSCs when injected with tetramethyl rhodamine isothiocyanate dextran (79). The authors described that this increased permeability was mediated by elevated nitric oxide (NO) levels via endothelial nitric oxide synthase. Moreover, treatment with a NO synthase inhibitor reduced vascular leakiness, suggesting that targeting the BM microenvironment through co-therapeutic strategies could help restore altered histology in MPNs. Nonetheless, the potential increase in sinusoidal leakiness or permeability within the BM during MPN progression demands further research.
The spleen and liver serve as primary sites of EMH, and palpable splenomegaly is a consistent histopathological feature observed in MPNs and other leukemias (80, 81). A study involving 24 MPN patients harboring the JAK2V617F mutation revealed distinct splenic histopathological patterns, including diffuse, micronodular, and mixed nodular forms of hematopoiesis (82), further supporting the role of JAK2V617F in altering splenic architecture during MPN progression. Similarly, Tie2-Cre mice expressing JAK2V617F in both HSCs and ECs also developed splenomegaly (30, 83), suggesting that additional mutations or alterations within the vasculature may further contribute to this phenotype. Overall, the spleen functions as a compensatory site of EMH during BM niche dysregulation, and it remains intriguing to elucidate how the JAK2V617F mutation specifically modifies the cellular and vascular morphology of the spleen to promote MPN pathogenesis.
Adhesion/pro-adherent interaction of HSCs and niche in MPN
HSC malignancies are clinically associated with perturbed thrombotic events, characterized by excessive numbers of functionally abnormal red cells, platelets, and leukocytes within the veins and arterioles of the various organs (84). Recent evidence from surgical thrombectomy specimens demonstrated that direct cell to cell contact between platelets and RBCs occurs via the FasL/FasR pathway, suggesting that RBC-platelet interactions may further enhance thrombotic events (85). In addition, conditional JAK2V617F knock in mice showed that neutrophils exhibit an increased propensity for neutrophil extracellular trap (NET) formation, which facilitates thrombosis (86). Furthermore, JAK2V617F bearing HSC and monocytes display increased activation and enhanced affinity of integrin molecules (e.g., VLA-4 and LFA-1) toward endothelial adhesion receptors such as PECAM1 and ICAM1, indicating that thrombosis is not restricted to platelets alone, but that other JAK2V617F positive hematopoietic and niche cells also contribute to the enhanced thrombotic phenotype during MPN progression (87). Moreover, increased pro-adherent properties and expression of adhesion molecules such as P-selectin have been reported in JAK2V617F bearing ECs of the splenic vein in Budd–Chiari syndrome, as well as in PDGFb-Cre ECs and iPSC derived ECs (27, 31, 32). Together, these findings support the hypothesis that JAK2V617F bearing cells provide extrinsic pro-thrombotic support, promoting disease progression through enhanced pro-adherent interactions within the vascular niche.
Altered physiology and metabolic conditions of HSCs and the niche
The self-renewal activity of LT-HSCs and their ability to generate terminally differentiated cells within the BM microenvironment depend strongly on physiological factors such as maintenance of hypoxia. An in vitro study by Mitsumori et al. (2014) demonstrated that hypoxic conditions inhibit phosphorylation of JAK2V617F through inactivation of SHP-2, thereby promoting quiescence in HSCs (88). Conversely, accumulation of reactive oxygen species (ROS) within the HSC compartment, and subsequent treatment with antioxidants, were shown to reduce hematopoiesis in both the spleen and BM of JAK2V617F knock in mice, suggesting that varying oxygen concentrations and ROS levels may play critical roles in HSC expansion during JAK2V617F driven disease (89). In addition, hypoxia inducible factor (HIF), a major regulator of oxidative phosphorylation, was shown to be essential for the growth and expansion of JAK2V617F expressing 32D cells and MPN patient derived iPSCs (90), support relation of hypoxic environment within HSCs niche. Moreover, increased glucose uptake, upregulated glycolysis, and enhanced nitrogen metabolism represent metabolic features common to most cancers, including JAK2V617F mutant cells. Consistent with this, significant inhibition of JAK2V617F driven cellular phenotypes was achieved by targeting 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) and glutaminase (91, 92). Together, these findings indicate that altered physiological and metabolic states, particularly those involving hypoxia, ROS balance, and metabolic reprogramming play crucial roles in MPN disease progression, providing new avenues for therapeutic exploration.
Ruxolitinib failure and therapeutic strategies in MPN
Treatment decisions for MPN are generally based on MPN subtype, risk category, age, and disease manifestations. Identification of the key role of JAK2V617F mutation and JAK2 inhibitor such as ruxolitinib remained pivotal in the treatment of MPN. Mostly, ruxolitinib is found to improve overall symptoms and reduces the spleen size in MPN patients. In addition, other advanced phase JAK inhibitors targeting JAK2 or related pathways such as momelotinib, pacritinib, and fedratinib have demonstrated similar effects, reducing splenomegaly and myelofibrosis related symptoms by inhibiting JAK1/2, JAK2/FLT3, and JAK2 kinases, respectively (93–95). However, JAK inhibitor monotherapy remains only partially effective because of the heterogeneous contributors to MPN progression, and ruxolitinib often loses efficacy over time. It has been proposed that ruxolitinib resistance may transiently facilitate transplant engraftment, but sustained resistance within the cellular microenvironment can result in aggressive disease relapse (96). Moreover, since JAK2 inhibitors target central HSCs signaling pathways, they can also impair succeeding progenitor cell survival, leading to adverse events such as anemia, thrombocytopenia, and increased infection risk due to impaired dendritic cell function (97). Therefore, new strategies are needed that move beyond JAK2 pathway inhibition. Nonetheless, JAK2 targeted therapy remains beneficial in reducing splenomegaly and may serve effectively in combination with other microenvironment or pathway targeted therapies.
Epigenetic regulation has also emerged as an important therapeutic focus in MPN. For example, miR-375, a negative regulator of the JAK-STAT pathway that is downregulated in MPN. It has been shown therapeutic promise when its expression is restored by targeting histone methylation pathways using histone deacetylase inhibitors such as trichostatin A and vorinostat (98). Moreover, numerous clinical trials are ongoing, evaluating drugs that target histone methylation, PI3K/AKT/mTOR, or other signaling pathways, either alone or in combination with ruxolitinib. Additionally, IFN-α remains another standard treatment, showing up to 80% response rates in PV and ET patients. However, its clinical use is often limited by adverse effects such as cytopenias, flu-like symptoms, and fatigue, necessitating treatment discontinuation.
Ruxolitinib treatment failure generally arises through two main mechanisms: (a) drug related side effects, and (b) acquired resistance. For side effects, many patients require prolonged dosing, but higher doses often induce headache, dizziness, and anemia. Dose optimization therefore remains critical given patient heterogeneity. To elucidate mechanisms of ruxolitinib resistance, a study analyzing 95 MF patients revealed frequent mutations across 15 genes other than JAK2, suggesting that treatment failure may also result from additional co-occurring other mutations (99, 100). Interestingly, although JAK2V617F is the primary mutation, no secondary mutations yet have been identified in the JAK2 kinase domain of ruxolitinib resistant patients (101), indicating that ruxolitinib resistance may develop via other than JAK2 gene mutation. Alternative hypotheses include compensatory activation of other JAK family members could happen (such as JAK1 or TYK2) during ruxolitinib therapy. All together, these findings underscore the urgent need to explain the molecular basis of ruxolitinib resistance and identify combinatorial therapeutic strategies to achieve justified and more durable MPN control.
Targeting the altered HSC microenvironment through chemotherapy
With the emerging resistance to JAK inhibitors, other signaling pathways that targeted mono or combination drugs strategies focusing on the hematopoietic niche are gaining attention in MPN treatment (as represented in Figure 1). Among the key cytokines, TGF-β1 is notably elevated in PMF and plays a dual role in the fibrotic and proliferative aspects of myelofibrosis. Sotatercept, a first in class activin receptor type IIA (ActRIIA) ligand trap, sequesters TGF-β ligands and has been shown to improve erythropoiesis in PMF patients (102). Therefore, incorporating such agents in combination with ruxolitinib could potentially extend the therapeutic benefits in MPN. A limited clinical study using fresolimumab, an anti-TGF-β immunoglobulin (phase I trial), demonstrated halted disease progression for up to 12 cycles without observed toxicity (103) (102). Although the trial was discontinued at the management level, these findings strongly support the feasibility of targeting TGF-β signaling as a therapeutic strategy in MPN.
Another important target within the fibrotic niche is lysyl oxidase (LOX), a matrix cross-linking enzyme secreted by MKs that oxidizes PDGF and contributes to MF progression. Inhibition of LOX using β-aminopropionitrile significantly improved bone marrow fibrosis and reduced splenic MK counts (104). Furthermore, two new LOX inhibitors, PXS-LOX-1 and PXS-LOX-2, were tested in GATA1low and JAK2V617F mouse models with PMF phenotypes, demonstrating reduced fibrotic burden and MK numbers (105). These results suggest that targeting LOX in immature MKs could represent a promising therapeutic avenue for MPN.
Other promising agent, PRM-151 (human serum amyloid P or PTX-2), a recombinant protein in phase II clinical evaluation, regulates monocyte differentiation into fibrocytes and profibrotic macrophages at damaged sites. Clinical data indicated a 23% reduction in fibrosis, along with improvements in anemia (40%), spleen size (26%), and disease related symptoms (38%) in patients treated with PRM-151 (102). Although a phase II trial demonstrated clinical benefit over 28 weeks in patients with idiopathic pulmonary fibrosis, the phase III trial did not meet its primary endpoint, showing no significant advantage over placebo (106). Nevertheless, targeting the MK derived extracellular matrix and the fibrotic bone marrow microenvironment using agents such as PRM-151 could remain a promising alternative therapeutic strategy for MPN management.
The CXCR4-CXCL12 axis plays a crucial role in HSCs homing and retention within the bone marrow. Plerixafor, a CXCR4 antagonist, is widely used (with G-CSF) for mobilizing HSCs into the peripheral blood for autologous transplantation in non-Hodgkin’s lymphoma and multiple myeloma patients (107). Moreover, the anti-CXCR4 antibody MDX-1338 disrupts the CXCL12-CXCR4 interaction by inducing calcium flux, leading to apoptosis of tumor cells (107). Given that CXCR4-CXCL12 signaling is upregulated in MPN (30, 53), this pathway represents a viable therapeutic target. Early clinical trials with MDX-1338 in 40 AML patients (phase I) reported no major adverse effects (107), and recent studies have shown that blocking CXCR4 can trigger ROS mediated, caspase independent apoptosis in chronic lymphocytic leukemia cells (108). Thus, targeting CXCR4-CXCL12 using plerixafor, G-CSF, or MDX-1338 could offer therapeutic benefit by modulating HSC mobilization and suppressing malignant cell proliferation in MPN.
Additionally, HIF-1α, which is highly expressed in HSCs under normoxic conditions, has been identified as a potential target. Echinomycin, a HIF-1α inhibitor, suppresses JAK2V617F cell growth by inducing hypoxia (90). Similarly, PX-478, another HIF-1α inhibitor, has shown multiple effects, including induction of apoptosis and inhibition of VEGF production, thereby indirectly regulating HSC self-renewal (109). Manipulating oxygen dependent pathways through HIF-1α inhibition may thus provide a novel therapeutic direction, as it directly links metabolic regulation with stem cell proliferation in MPN disease.
Finally, metabolic targeting approaches have also gained attention to MPN treatment. For example, glutamine synthesis is upregulated in JAK2V617F mutant cells, and treatment with the glutaminase inhibitor BPTES in combination with ruxolitinib enhanced the antiproliferative effects in both mutant cell lines and MPN patient derived CD34+ cells (92). Since glycolytic and nitrogen metabolism rates are elevated in JAK2V617F mutant cells (a phenomenon consistent with the Warburg effect), investigating these selective metabolic pathways either alone or in combination with JAK inhibitors could lead to improved therapeutic outcomes for MPN patients.
Conclusion
The bone marrow niche is crucial to both normal hematopoiesis and MPN pathogenesis. JAK2V617F mutant HSCs remodel this niche by altering cytokine signaling, metabolism, and cellular interactions, driving disease progression. Targeting these abnormal niche factors, such as TGF-β, CXCL12/CXCR4, the extracellular matrix, and metabolic pathways, may have therapeutic potential beyond symptomatic relief. BM-niche focused therapies may restore normal hematopoiesis, prevent EMH, overcome JAK2 inhibitor resistance, and improve overall MPN treatment response. Although many dysregulated signaling and metabolic pathways are reviewed here, key questions remain regarding which niche-derived signals are primary drivers versus secondary consequences, and how best to translate niche-targeted strategies into durable therapies. By integrating recent findings and outlining these unresolved challenges, future therapies that directly target this niche factors could address the root causes of MPNs and provide more effective and lasting outcomes, highlighting the critical contribution of this review to the field.
Author contributions
AY: Conceptualization, Data curation, Formal Analysis, Investigation, Writing – original draft, Writing – review & editing.
Funding
The author(s) declared that financial support was not received for this work and/or its publication.
Acknowledgments
I am thankful to Dr. H. Zhan for the initial convenience of the draft.
Conflict of interest
The authors declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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Keywords: JAK2V617F, MPN, bone marrow microenvironment, HSCs, cytokines, chemokines
Citation: Yeware A (2026) Targeting the JAK2V617F mutant hematopoietic microenvironment in myeloproliferative neoplasm. Front. Hematol. 4:1694867. doi: 10.3389/frhem.2025.1694867
Received: 29 August 2025; Accepted: 08 December 2025; Revised: 21 November 2025;
Published: 08 January 2026.
Edited by:
Andrew J. Innes, Imperial College London, United KingdomReviewed by:
Giulia Pozzi, University of Parma, ItalyEman Khatib-Massalha, University of Cambridge, United Kingdom
Copyright © 2026 Yeware. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Amar Yeware, YW1hcnlld2FyZTAwN0BnbWFpbC5jb20=; eWV3YXJlQHdpc2MuZWR1