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Effect of NS-018, a selective JAK2V617F inhibitor, in a murine model of myelofibrosis.

ABSTRACT: A single somatic mutation, V617F, in Janus kinase 2 (JAK2) is one of the causes of myeloproliferative neoplasms (MPNs), including primary myelofibrosis, and the JAK2V617F mutant kinase is a therapeutic target in MPN. However, inhibition of wild-type (WT) JAK2 can decrease the erythrocyte or platelet (PLT) count. Our selective JAK2 inhibitor, NS-018, suppressed the growth of Ba/F3 cells harboring JAK2V617F more strongly than that of cells harboring WT JAK2. The 4.3-fold JAK2V617F selectivity of NS-018 is higher than the 1.0- to 2.9-fold selectivity of seven existing JAK2 inhibitors. NS-018 also inhibited erythroid colony formation in JAK2V617F transgenic mice at significantly lower concentrations than in WT mice. In keeping with the above results, in a JAK2V617F bone marrow transplantation mouse model with a myelofibrosis-like disease, NS-018 reduced leukocytosis and splenomegaly, improved bone marrow fibrosis and prolonged survival without decreasing the erythrocyte or PLT count in the peripheral blood. By exploring the X-ray co-crystal structure of NS-018 bound to JAK2, we identified unique hydrogen-bonding interactions between NS-018 and Gly993 as a plausible explanation for its JAK2V617F selectivity. These results suggest that NS-018 will have therapeutic benefit for MPN patients through both its efficacy and its reduced hematologic adverse effects.

SUBMITTER: Nakaya Y

PROVIDER: S-EPMC3913942 | biostudies-literature |

REPOSITORIES: biostudies-literature

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A phase I, open-label, dose-escalation, multicenter study of the JAK2 inhibitor NS-018 in patients with myelofibrosis.

Project description:NS-018 is a Janus-activated kinase 2 (JAK2)-selective inhibitor, targeting the JAK-signal transducer and activator of transcription (STAT) pathway that is deregulated in myelofibrosis. In this phase I, dose-escalation portion of a phase I/II study, patients with myelofibrosis received oral NS-018 in continuous 28-day cycles. The primary study objective was to evaluate safety, tolerability and clinically active dose of NS-018. Forty-eight patients were treated; 23 (48%) had previously received a JAK inhibitor (JAKi). The most common drug-related adverse events were thrombocytopenia (27%)/anemia (15%) for hematologic events, and dizziness (23%)/nausea (19%) for non-hematologic events. Once daily NS-018 at 300?mg was chosen as the phase II study dose based on improved tolerability compared with higher doses. A ?50% reduction in palpable spleen size was achieved in 56% of patients (47% of patients with prior JAKi treatment), and improvements were observed in myelofibrosis-associated symptoms. Bone marrow fibrosis grade (local assessment) improved from baseline in 11/30 evaluable patients (37%) after 3 cycles of NS-018. JAK2 allele burden was largely unchanged. Changes in cytokine/protein levels were noted after 4 weeks of treatment. NS-018 reached peak plasma concentration in 1-2?h and did not accumulate with multiple dosing. NS-018 will be assessed in patients with previous JAKi exposure in the phase II portion.

| S-EPMC5292677 | biostudies-literature

Efficacy of NS-018, a potent and selective JAK2/Src inhibitor, in primary cells and mouse models of myeloproliferative neoplasms.

Project description:Aberrant activation of Janus kinase 2 (JAK2) caused by somatic mutation of JAK2 (JAK2V617F) or the thrombopoietin receptor (MPLW515L) plays an essential role in the pathogenesis of myeloproliferative neoplasms (MPNs), suggesting that inhibition of aberrant JAK2 activation would have a therapeutic benefit. Our novel JAK2 inhibitor, NS-018, was highly active against JAK2 with a 50% inhibition (IC(50)) of <1?n, and had 30-50-fold greater selectivity for JAK2 over other JAK-family kinases, such as JAK1, JAK3 and tyrosine kinase 2. In addition to JAK2, NS-018 inhibited Src-family kinases. NS-018 showed potent antiproliferative activity against cell lines expressing a constitutively activated JAK2 (the JAK2V617F or MPLW515L mutations or the TEL-JAK2 fusion gene; IC(50)=11-120?n), but showed only minimal cytotoxicity against most other hematopoietic cell lines without a constitutively activated JAK2. Furthermore, NS-018 preferentially suppressed in vitro erythropoietin-independent endogenous colony formation from polycythemia vera patients. NS-018 also markedly reduced splenomegaly and prolonged the survival of mice inoculated with Ba/F3 cells harboring JAK2V617F. In addition, NS-018 significantly reduced leukocytosis, hepatosplenomegaly and extramedullary hematopoiesis, improved nutritional status, and prolonged survival in JAK2V617F transgenic mice. These results suggest that NS-018 will be a promising candidate for the treatment of MPNs.

| S-EPMC3255248 | biostudies-literature

Expression of Jak2V617F causes a polycythemia vera-like disease with associated myelofibrosis in a murine bone marrow transplant model.

Project description:An acquired somatic mutation, Jak2V617F, was recently discovered in most patients with polycythemia vera (PV), chronic idiopathic myelofibrosis (CIMF), and essential thrombocythemia (ET). To investigate the role of this mutation in vivo, we transplanted bone marrow (BM) transduced with a retrovirus expressing either Jak2 wild-type (wt) or Jak2V617F into lethally irradiated syngeneic recipient mice. Expression of Jak2V617F, but not Jak2wt, resulted in clinicopathologic features that closely resembled PV in humans. These included striking elevation in hemoglobin level/hematocrit, leukocytosis, megakaryocyte hyperplasia, extramedullary hematopoiesis resulting in splenomegaly, and reticulin fibrosis in the bone marrow. Histopathologic and flow cytometric analyses showed an increase in maturing myeloid lineage progenitors, although megakaryocytes showed decreased polyploidization and staining for acetylcholinesterase. In vitro analysis of primary cells showed constitutive activation of Stat5 and cytokine-independent growth of erythroid colony-forming unit (CFU-E) and erythropoietin hypersensitivity, and Southern blot analysis for retroviral integration indicated that the disease was oligoclonal. Furthermore, we observed strain-specific differences in phenotype, with Balb/c mice demonstrating markedly elevated leukocyte counts, splenomegaly, and reticulin fibrosis compared with C57Bl/6 mice. We conclude that Jak2V617F expression in bone marrow progenitors results in a PV-like syndrome with myelofibrosis and that there are strain-specific modifiers that may in part explain phenotypic pleiotropy of Jak2V617F-associated myeloproliferative disease in humans.

| S-EPMC1895786 | biostudies-literature

Captopril mitigates splenomegaly and myelofibrosis in the Gata1low murine model of myelofibrosis.

Project description:Allogeneic stem cell transplantation is currently the only curative therapy for primary myelofibrosis (MF), while the JAK2 inhibitor, ruxolitinib. Has been approved only for palliation. Other therapies are desperately needed to reverse life-threatening MF. However, the cell(s) and cytokine(s) that promote MF remain unclear. Several reports have demonstrated that captopril, an inhibitor of angiotensin-converting enzyme that blocks the production of angiotensin II (Ang II), mitigates fibrosis in heart, lung, skin and kidney. Here, we show that captopril can mitigate the development of MF in the Gata1low mouse model of primary MF. Gata1low mice were treated with 79 mg/kg/d captopril in the drinking water from 10 to 12 months of age. At 13 months of age, bone marrows were examined for fibrosis, megakaryocytosis and collagen expression; spleens were examined for megakaryocytosis, splenomegaly and collagen expression. Treatment of Gata1low mice with captopril in the drinking water was associated with normalization of the bone marrow cellularity; reduced reticulin fibres, splenomegaly and megakaryocytosis; and decreased collagen expression. Our findings suggest that treating with the ACE inhibitors captopril has a significant benefit in overcoming pathological changes associated with MF.

| S-EPMC6111823 | biostudies-other

Effect of treatment with a JAK2-selective inhibitor, fedratinib, on bone marrow fibrosis in patients with myelofibrosis.

Project description:BackgroundProgressive bone marrow fibrosis (BMF) is a cardinal feature of many myeloproliferative neoplasms (MPNs) and there is a documented association between the severity of BMF and overall prognosis. We conducted an exploratory analysis of sequential BMF data from two phase I studies of long-term treatment with the Janus kinase 2 (JAK2) inhibitor fedratinib in patients with myelofibrosis.MethodsBone marrow samples were obtained at baseline and after every six cycles (24 weeks) of daily fedratinib treatment. Fibrosis was centrally assessed by three independent haematopathologists, who were blinded to the patients' data, and graded according to European Consensus Myelofibrosis Grading Criteria. The analysis population comprised patients with a baseline BMF grade ≥1, and at least one post-baseline BMF grade assessment. Changes in BMF grade compared with baseline were classified as improvement (≥1 grade reduction), stabilisation (no change in any baseline BMF grade <3) or worsening (≥1 grade increase).ResultsTwenty-one patients were included in the analysis. A total of 153 bone marrow samples were analysed. Improvement or stabilisation of BMF from baseline was recorded in 15 of 18 (83%) evaluable patients at cycle 6 and in four of nine (44%) evaluable patients at cycle 30. Two patients achieved resolution of their BMF (grade = 0) by cycle 12.ConclusionsThis exploratory analysis indicates that improvement or even resolution of BMF may be achievable with JAK2 inhibitor therapy in some patients with MPNs and myelofibrosis.

| S-EPMC4566296 | biostudies-literature

Safety and efficacy of TG101348, a selective JAK2 inhibitor, in myelofibrosis.

Project description:PurposeMyelofibrosis is a myeloid malignancy associated with anemia, splenomegaly, and constitutional symptoms. Patients frequently harbor JAK-STAT activating mutations that are sensitive to TG101348, a selective small-molecule Janus kinase 2 (JAK2) inhibitor.Patients and methodsIn a multicenter phase I trial, oral TG101348 was administered once a day to patients with high- or intermediate-risk primary or post-polycythemia vera/essential thrombocythemia myelofibrosis.ResultsFifty-nine patients were treated, including 28 in the dose-escalation phase. The maximum-tolerated dose was 680 mg/d, and dose-limiting toxicity was a reversible and asymptomatic increase in the serum amylase level. Forty-three patients (73%) continued treatment beyond six cycles; the median cumulative exposure to TG101348 was 380 days. Adverse events included nausea, vomiting, diarrhea, anemia, and thrombocytopenia; corresponding grades 3 to 4 incidence rates were 3%, 3%, 10%, 35%, and 24%. TG101348 treatment had modest effect on serum cytokine levels, but greater than half of the patients with early satiety, night sweats, fatigue, pruritus, and cough achieved rapid and durable improvement in these symptoms. By six and 12 cycles of treatment, 39% and 47% of patients, respectively, had achieved a spleen response per International Working Group criteria. The majority of patients with leukocytosis or thrombocytosis at baseline (n = 28 and n = 10, respectively) achieved normalization of blood counts after six (57% and 90%, respectively) and 12 (56% and 88%, respectively) cycles. A significant decrease in JAK2 V617F allele burden was observed at 6 months in mutation-positive patients (n = 51; P = .04), particularly in the subgroup with allele burden greater than 20% (n = 23; P < .01); the decrease was durable at 12 months.ConclusionTG101348 is well tolerated and produces significant reduction in disease burden and durable clinical benefit in patients with myelofibrosis.

| S-EPMC4979099 | biostudies-literature

Loss of Ezh2 cooperates with Jak2V617F in the development of myelofibrosis in a mouse model of myeloproliferative neoplasm.

Project description:An activating JAK2V617F mutation has been found in ∼50% patients with myelofibrosis (MF). Inactivating mutations in histone methyltransferase enhancer of zeste homolog 2 (EZH2) also have been observed in patients with MF. Interestingly, inactivating EZH2 mutations are often associated with JAK2V617F mutation in MF, although their contributions in the pathogenesis of MF remain elusive. To determine the effects of concomitant loss of EZH2 and JAK2V617F mutation in hematopoiesis, we generated Ezh2-deficient Jak2V617F-expressing mice. Whereas expression of Jak2V617F alone induced a polycythemia vera-like disease, concomitant loss of Ezh2 significantly reduced the red blood cell and hematocrit parameters but increased the platelet counts in Jak2V617F knock-in mice. Flow cytometric analysis showed impairment of erythroid differentiation and expansion of megakaryocytic precursors in Ezh2-deficient Jak2V617F mice. Moreover, loss of Ezh2 enhanced the repopulation capacity of Jak2V617F-expressing hematopoietic stem cells. Histopathologic analysis revealed extensive fibrosis in the bone marrow (BM) and spleen of Ezh2-deleted Jak2V617F mice. Transplantation of BM from Ezh2-deleted Jak2V617F mice into wild-type animals resulted in even faster progression to MF. Gene expression profiling and chromatin immunoprecipitation sequence analysis revealed that S100a8, S100a9, Ifi27l2a, and Hmga2 were transcriptionally derepressed, and the H3K27me3 levels in these gene promoters were significantly reduced on Ezh2 deletion in hematopoietic progenitors of Jak2V617F mice. Furthermore, overexpression of S100a8, S100a9, Ifi27l2a, or Hmga2 significantly increased megakaryocytic colonies in the BM of Jak2V617F mice, indicating a role for these Ezh2 target genes in altered megakaryopoiesis involved in MF. Overall, our results suggest that loss of Ezh2 cooperates with Jak2V617F in the development of MF in Jak2V617F-expressing mice.

| S-EPMC4929929 | biostudies-literature

Immunoproteasome Genes Are Modulated in CD34+ JAK2V617F Mutated Cells from Primary Myelofibrosis Patients.

Project description:Primary myelofibrosis (PMF) is a rare myeloproliferative neoplasm characterized by stem-cell-derived clonal over-proliferation of mature myeloid lineages, bone marrow fibrosis, osteosclerosis, defective erythropoiesis, and pro-inflammatory cytokine over-expression. The aim of the present study was to highlight possible differences in the transcriptome among CD34+ cells from peripheral blood (PB) of PMF patients. Therefore, we merged two microarray datasets of healthy control subjects and PMF (34 JAK2V617F MUTATED and 28 JAK2 wild-type). The GO analysis of upregulated genes revealed enrichment for JAK2/STAT1 pathway gene set in PB CD34+ cells of PMF patients with and without the JAK2V617F mutation comparing to the healthy control subjects, and in particular a significant upregulation of immunoproteasome (IP)-belonging genes as PSMB8, PSMB9, and PSMB10. A more detailed investigation of the IFN-gamma (IFNG) pathway also revealed that IFNG, IRF1, and IFNGR2 were significantly upregulated in PB CD34+ cells of PMF patients carrying the mutation for JAK2V617F compared to JAK2 wild-type PMF patients. Finally, we showed an upregulation of HLA-class I genes in PB CD34+ cells from PMF JAK2V617F mutated patients compared to JAK2 wild-type and healthy controls. In conclusion, our results demonstrate that IPs and IFNG pathways could be involved in PMF disease and in particular in patients carrying the JAK2V617F mutation.

| S-EPMC7216198 | biostudies-literature

JAK2V617F Mutant Megakaryocytes Contribute to Hematopoietic Aging in a Murine Model of Myeloproliferative Neoplasm.

Project description:Megakaryocytes (MKs) is an important component of the hematopoietic niche. Abnormal MK hyperplasia is a hallmark feature of myeloproliferative neoplasms (MPNs). The JAK2V617F mutation is present in hematopoietic cells in a majority of patients with MPNs. Using a murine model of MPN in which the human JAK2V617F gene is expressed in the MK lineage, we show that the JAK2V617F-bearing MKs promote hematopoietic stem cell (HSC) aging, manifesting as myeloid-skewed hematopoiesis with an expansion of CD41+ HSCs, a reduced engraftment and self-renewal capacity, and a reduced differentiation capacity. HSCs from 2-year-old mice with JAK2V617F-bearing MKs were more proliferative and less quiescent than HSCs from age-matched control mice. Examination of the marrow hematopoietic niche reveals that the JAK2V617F-bearing MKs not only have decreased direct interactions with hematopoietic stem/progenitor cells during aging but also suppress the vascular niche function during aging. Unbiased RNA expression profiling reveals that HSC aging has a profound effect on MK transcriptomic profiles, while targeted cytokine array shows that the JAK2V617F-bearing MKs can alter the hematopoietic niche through increased levels of pro-inflammatory and anti-angiogenic factors. Therefore, as a hematopoietic niche cell, MKs represent an important connection between the extrinsic and intrinsic mechanisms for HSC aging.

| S-EPMC9199841 | biostudies-literature

Pacritinib demonstrates spleen volume reduction in patients with myelofibrosis independent of JAK2V617F allele burden.

Project description:Myelofibrosis (MF) has heterogeneous clinical manifestations, with some patients exhibiting a myelodepletive phenotype characterized by cytopenias and an absent or low JAK2V617F allele burden. Ruxolitinib may be less effective in these patients. We assessed the efficacy of pacritinib, a JAK2/IRAK1 inhibitor, in MF patients with low JAK2V617F allele burden. In this post hoc analysis of the PERSIST-1 and -2 trials, patients with MF randomized to pacritinib or best available therapy (BAT) were stratified by JAK2V617F allele burden quartile for spleen response of ≥35% and improvement in total symptom score of ≥50%. Five hundred thirty-six patients were included. Patients with lower JAK2V617F allele burden had smaller baseline spleens and lower hemoglobin and platelet counts as compared with higher allele burden patients. Among pacritinib-treated patients, spleen responses were observed across all JAK2V617F allele burden quartiles and in JAK2V617F- disease. No spleen responses were observed among BAT-treated patients with allele burden ≤50% or JAK2V617F- disease. The intention-to-treat response rate was significantly higher on the pacritinib arm for JAK2V617F- disease (23.0% vs 0%; P = .033), and for the lowest allele burden quartiles (0%-25%: 20.9% vs 0%, P < .001; 25%-50%: 15.4% vs 0%, P = .020). There were significantly more symptom responders with pacritinib vs BAT in the 0% to 25% and 25% to 50% cohorts. Pacritinib treatment led to superior spleen and symptom burden reduction compared with BAT in patients with absent or low JAK2V617F allele burden, suggesting that pacritinib may be uniquely suited for patients with myelodepletive MF.

| S-EPMC7724916 | biostudies-literature

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