Unplugging JAK/STAT in Chronic Myelomonocytic Leukemia

Solary, Éric

doi:10.1158/1078-0432.ccr-16-0372

Cited by 9 publications

(3 citation statements)

References 12 publications

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“…87,88 Therapeutic approaches targeting this signaling pathway are currently being assessed, 89 including the use of ruxolitinib that could control inflammatory symptoms (Table 3). 90 Extramedullary disease MPN-CMML patients can experience constitutional symptoms, including fatigue, diffuse bone pain, and night sweats, and develop a splenomegaly (;30% of cases), which is occasionally troublesome, resulting from extramedullary hematopoiesis.…”

Section: Myeloproliferative Cmmlmentioning

confidence: 99%

How I treat chronic myelomonocytic leukemia

Solary

Itzykson

2017

Blood

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Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic malignancy that may deserve specific management. Defined by a persistent peripheral blood monocytosis ≥1 × 109/L and monocytes accounting for ≥10% of the white blood cells, this aging-associated disease combines cell proliferation as a consequence of myeloid progenitor hypersensitivity to granulocyte-macrophage colony-stimulating factor with myeloid cell dysplasia and ineffective hematopoiesis. The only curative option for CMML remains allogeneic stem cell transplantation. When transplantation is excluded, CMML is stratified into myelodysplastic (white blood cell count <13 × 109/L) and proliferative (white blood cell count ≥13 × 109/L) CMML. In the absence of poor prognostic factors, the management of myelodysplastic CMML is largely inspired from myelodysplastic syndromes, relying on erythropoiesis-stimulating agents to cope with anemia, and careful monitoring and supportive care, whereas the management of proliferative CMML usually relies on cytoreductive agents such as hydroxyurea, although ongoing studies will help delineate the role of hypomethylating agents in this patient population. In the presence of excessive blasts and other poor prognostic factors, hypomethylating agents are the preferred option, even though their impact on leukemic transformation and survival has not been proved. The therapeutic choice is illustrated by 4 clinical situations among the most commonly seen. Although current therapeutic options can improve patient’s quality of life, they barely modify disease evolution. Improved understanding of CMML pathophysiology will hopefully lead to the exploration of novel targets that potentially would be curative.

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Section: Myeloproliferative Cmmlmentioning

confidence: 99%

How I treat chronic myelomonocytic leukemia

Solary

Itzykson

2017

Blood

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“…Previous studies have shown that the JAK-STAT signaling pathway is an important cascade mediating the effects of a wide range of cytokines such as transforming growth factor beta (TGF-β) [ 9 , 10 ], platelet-derived growth factor (PDGF) [ 11 ], interleukin (IL) 6 [ 12 ], and granulocyte colony-stimulating growth factor (G-CSF) [ 13 ]. Blocking the effects of these cytokines leads to a decrease in collagen synthesis, suppression of the proliferation of smooth muscle cells, fibroblasts, endotheliocytes, and an anti-inflammatory effect.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of JAK1,2 Prevents Fibrotic Remodeling of Pulmonary Vascular Bed and Improves Outcomes in the Rat Model of Chronic Thromboembolic Pulmonary Hypertension

Карпов

Mihailova

Shilenko

et al. 2022

IJMS

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Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare complication of acute pulmonary embolism with poor clinical outcomes. Therapeutic approaches to prevention of fibrotic remodeling of the pulmonary vascular bed in CTEPH are limited. In this work, we tested the hypothesis that Janus kinase 1/2 (JAK1/2) inhibition with ruxolitinib might prevent and attenuate CTEPH in a rat model. CTEPH was induced by repeated embolization of the pulmonary artery with partially biodegradable 180 ± 30 μm alginate microspheres. Two weeks after the last injection of microspheres, ruxolitinib was administered orally at doses of 0.86, 2.58, and 4.28 mg/kg per day for 4 weeks. Prednisolone (1.475 mg/kg, i.m.) was used as a reference drug. Ruxolitinib in all doses as well as prednisolone reduced pulmonary vascular wall hypertrophy. Ruxolitinib at a dose of 2.58 mg/kg and prednisolone reduced vascular wall fibrosis. Prednisolone treatment resulted in decreased right ventricular systolic pressure. Pulmonary vascular resistance was lower in the prednisolone and ruxolitinib (4.28 mg/kg) groups in comparison with the placebo group. The plasma level of brain natriuretic peptide was lower in groups receiving ruxolitinib at doses of 2.58 and 4.28 mg/kg versus placebo. This study demonstrated that JAK1/2 inhibitor ruxolitinib dose-dependently reduced pulmonary vascular remodeling, thereby preventing CTEPH formation in rats.

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“…В ранее проведенных исследованиях было показано, что JAK-STAT-сигнальный путь является важным каскадом, опосредующим эффекты широкого спектра цитокинов, таких как TGF-β [4, 5], тромбоцитарного фактора роста (PDGF) [6], интерлейкина (ИЛ) 6 [7], гранулоцитарного колониестимулирующего фактора роста (G-CSF) [8]. Блокирование эффектов этих цитокинов приводит к снижению синтеза коллагена, подавлению пролиферации гладкомышечных клеток, фибробластов, эндотелиоцитов, противовоспалительному эффекту.…”

Section: Introductionunclassified

Study of the JAK inhibitors antifibrotic activity for the prevention and treatment of chronic thromboembolic pulmonary hypertension

Карпов

Vaulina

Mikhailova

et al. 2022

Regional blood circulation and microcirculation

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Introduction. Chronic thromboembolic pulmonary hypertension (CTEPH) is the most common complication of pulmonary thromboembolism (PE). Fibrous remodeling of the pulmonary circulation vessels against the background of CTEPH leads to an irreversible increase of the vessel wall stiffness and the ineffectiveness of CTEPH treatment. The involvement of Janus kinase (JAK) in the regulation of vascular wall and lung tissue inflammation and fibrosis allows for the possible effectiveness of JAK 1,2 inhibitors (iJAK) in the course of CTEPH. Purpose – to study the antifibrotic effect of iJAK for the prevention and treatment of CTEPH. Materials and methods. The study was conducted on male Wistar rats. Modeling of CTEPH was performed by sequential embolization of the vascular bed with partially biodegradable sodium alginate microspheres. 2 weeks after the last administration of the microspheres, low, medium and high doses of iJAK were initiated. To assess the effectiveness of the substance, the following tests were used: treadmill test, echocardiography, cardiac catheterization with right ventricular (RV) manometry, histological examination of the lungs. Results. Animals undergone vascular embolization demonstrated decreased exercise tolerance at all observation points compared to healthy animals. The placebo group, in contrast with the group getting treatment and iJAK, was found to have an increased mean RV pressure compared to healthy animals. There was an increase in mean RV pressure in the placebo group (15.5±7.7 mmHg) and in the low dose and iJAK group (13.4±6.4 mmHg) compared with healthy animals (9.4±2.2 mmHg). Vascular hypertrophy of the pulmonary artery branches was lower in group getting average dosages and iJAK compared with the placebo group (54.9±19.0 and 68.9±23.1 %, respectively). Thus, the suppression by iJAK of aseptic inflammation and following fibrosis leads to the decreasing of severity of pulmonary circulation remodeling in the experimental model of CTEPH. This approach can be used in the comprehensive bypass and prevention of CTEPH.

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Unplugging JAK/STAT in Chronic Myelomonocytic Leukemia

Cited by 9 publications

References 12 publications

How I treat chronic myelomonocytic leukemia

How I treat chronic myelomonocytic leukemia

Inhibition of JAK1,2 Prevents Fibrotic Remodeling of Pulmonary Vascular Bed and Improves Outcomes in the Rat Model of Chronic Thromboembolic Pulmonary Hypertension

Study of the JAK inhibitors antifibrotic activity for the prevention and treatment of chronic thromboembolic pulmonary hypertension

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