scholarly journals THE JAK2V617F POINT MUTATION INCREASES THE OSTEOCLAST FORMING ABILITY OF MONOCYTES IN PATIENTS WITH CHRONIC MYELOPROLIFERATIVE NEOPLASMS AND MAKES THEIR OSTEOCLASTS MORE SUSCEPTIBLE TO JAK2 INHIBITION

2018 ◽  
Vol 10 ◽  
pp. e2018058
Author(s):  
Emmanouil Spanoudakis ◽  
Menelaos Papoutselis ◽  
Ioanna Bazntiara ◽  
Eleftheria Lamprianidou ◽  
Xrisa Kordella ◽  
...  
Keyword(s):  
Point Mutation ◽  
Genomic Dna ◽  
Myeloproliferative Neoplasms ◽  
Myeloproliferative Neoplasm ◽  
Cellular Level ◽  
Hemopoietic Stem Cell ◽  
Jak2 Inhibitor ◽  
Chronic Myeloproliferative Neoplasms ◽  
Cell Niche ◽  
Jak2 Inhibition

JAK2V617F is a gain of function point mutation that occurs in Myeloproliferative Neoplasm (MPN) patients and deranges their hemopoiesis at cellular level. We speculate that hyperfunctioning JAK2 can modify osteoclast (OCL) homeostasis in MPN patients. We studied 18 newly diagnosed MPN patients and four age-matched normal donors (ND). Osteoclast forming assays started from selected monocytes also and under titrated concentrations of the JAK2 Inhibitor AG-490 (Tyrphostin). Genomic DNA was extracted from the formed osteoclasts, and the JAK2V617F/JAK2WT genomic DNA ratio was calculated. OCLs formed from monocytes derived from heterozygous (Het) for the JAK2V617F mutation MPN patients, were three times more compared to those from JAK2 wild type (WT) MPN patients (p=0,05) and from ND as well (p=0,03). The ratio of JAK2V617F/JAK2WT genomic DNA was increased in OCLs compared to the input monocyte cells showing a survival advantage of the mutated clone. In comparison to ND and JAK2 WT MPN patients, OCLs from patients JAK2V617F (Het) were more susceptible to JAK2 inhibition. These alterations in osteoclast homeostasis, attributed to mutated JAK2, can deregulate the hemopoietic stem cell niche in MPN patients.

scholarly journals Dual targeting of JAK2 and ERK interferes with the myeloproliferative neoplasm clone and enhances therapeutic efficacy

Leukemia ◽  
2021 ◽  
Author(s):  
Sime Brkic ◽  
Simona Stivala ◽  
Alice Santopolo ◽  
Jakub Szybinski ◽  
Sarah Jungius ◽  
...  
Keyword(s):  
Therapeutic Efficacy ◽  
Mapk Pathway ◽  
Myeloproliferative Neoplasms ◽  
Myeloproliferative Neoplasm ◽  
Term Treatment ◽  
Wild Type ◽  
Jak2 Inhibitor ◽  
Dual Targeting ◽  
Clinical Benefits ◽  
Jak2 Inhibition

AbstractMyeloproliferative neoplasms (MPN) show dysregulated JAK2 signaling. JAK2 inhibitors provide clinical benefits, but compensatory activation of MAPK pathway signaling impedes efficacy. We hypothesized that dual targeting of JAK2 and ERK1/2 could enhance clone control and therapeutic efficacy. We employed genetic and pharmacologic targeting of ERK1/2 in Jak2V617F MPN mice, cells and patient clinical isolates. Competitive transplantations of Jak2V617F vs. wild-type bone marrow (BM) showed that ERK1/2 deficiency in hematopoiesis mitigated MPN features and reduced the Jak2V617F clone in blood and hematopoietic progenitor compartments. ERK1/2 ablation combined with JAK2 inhibition suppressed MAPK transcriptional programs, normalized cytoses and promoted clone control suggesting dual JAK2/ERK1/2 targeting as enhanced corrective approach. Combined pharmacologic JAK2/ERK1/2 inhibition with ruxolitinib and ERK inhibitors reduced proliferation of Jak2V617F cells and corrected erythrocytosis and splenomegaly of Jak2V617F MPN mice. Longer-term treatment was able to induce clone reductions. BM fibrosis was significantly decreased in MPLW515L-driven MPN to an extent not seen with JAK2 inhibitor monotherapy. Colony formation from JAK2V617F patients’ CD34+ blood and BM was dose-dependently inhibited by combined JAK2/ERK1/2 inhibition in PV, ET, and MF subsets. Overall, we observed that dual targeting of JAK2 and ERK1/2 was able to enhance therapeutic efficacy suggesting a novel treatment approach for MPN.

scholarly journals Synergic Crosstalk between Inflammation, Oxidative Stress, and Genomic Alterations in BCR–ABL-Negative Myeloproliferative Neoplasm

Antioxidants ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 1037
Author(s):  
Alessandro Allegra ◽  
Giovanni Pioggia ◽  
Alessandro Tonacci ◽  
Marco Casciaro ◽  
Caterina Musolino ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Stem Cell ◽  
Chronic Inflammation ◽  
Myeloproliferative Neoplasms ◽  
Myeloproliferative Neoplasm ◽  
Tumor Stage ◽  
Driver Mutations ◽  
Hematopoietic Stem ◽  
Chronic Myeloproliferative Neoplasms ◽  
Inflammatory State

Philadelphia-negative chronic myeloproliferative neoplasms (MPNs) have recently been revealed to be related to chronic inflammation, oxidative stress, and the accumulation of reactive oxygen species. It has been proposed that MPNs represent a human inflammation model for tumor advancement, in which long-lasting inflammation serves as the driving element from early tumor stage (over polycythemia vera) to the later myelofibrotic cancer stage. It has been theorized that the starting event for acquired stem cell alteration may occur after a chronic inflammation stimulus with consequent myelopoietic drive, producing a genetic stem cell insult. When this occurs, the clone itself constantly produces inflammatory components in the bone marrow; these elements further cause clonal expansion. In BCR–ABL1-negative MPNs, the driver mutations include JAK 2, MPL, and CALR. Transcriptomic studies of hematopoietic stem cells from subjects with driver mutations have demonstrated the upregulation of inflammation-related genes capable of provoking the development of an inflammatory state. The possibility of acting on the inflammatory state as a therapeutic approach in MPNs appears promising, in which an intervention operating on the pathways that control the synthesis of cytokines and oxidative stress could be effective in reducing the possibility of leukemic progression and onset of complications.

scholarly journals What are the current treatment approaches for patients with polycythemia vera and essential thrombocythemia?

Hematology ◽  
2017 ◽  
Vol 2017 (1) ◽  
pp. 480-488 ◽  
Author(s):  
Alessandro M. Vannucchi ◽  
Paola Guglielmelli
Keyword(s):  
Polycythemia Vera ◽  
Essential Thrombocythemia ◽  
State Of The Art ◽  
Myeloproliferative Neoplasms ◽  
Symptom Burden ◽  
Current Treatment ◽  
Interferon Α ◽  
Jak2 Inhibitor ◽  
Chronic Myeloproliferative Neoplasms

Abstract Polycythemia vera (PV) and essential thrombocythemia (ET) are chronic myeloproliferative neoplasms that are characterized by thrombohemorrhagic complications, symptom burden, and impaired survival mainly due to thrombosis, progression to myelofibrosis, and transformation to acute leukemia. In this manuscript, we will review the most recent changes in diagnostic criteria, the improvements in risk stratification, and the “state of the art” in the daily management of these disorders. The role of conventional therapies and novel agents, interferon α and the JAK2 inhibitor ruxolitinib, is critically discussed based on the results of a few basic randomized clinical studies. Several unmet needs remain, above all, the lack of a curative approach that might overcome the still burdensome morbidity and mortality of these hematologic neoplasms, as well as the toxicities associated with therapeutic agents.

TET2 and ASXL1 Mutations in Leukemic Transformation of Chronic Myeloproliferative Neoplasms.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2894-2894 ◽  
Author(s):  
Omar Abdel-Wahab ◽  
Taghi Manshouri ◽  
Jay Patel ◽  
Kelly Harris ◽  
Jin Juan Yao ◽  
...  
Keyword(s):  
De Novo ◽  
Myeloproliferative Neoplasms ◽  
Myeloproliferative Neoplasm ◽  
Leukemic Transformation ◽  
Exact Test ◽  
Chronic Myeloproliferative Neoplasms ◽  
Secondary Acute Myeloid Leukemia ◽  
Paired Samples ◽  
Mutational Status ◽  
De Novo Aml

Abstract Abstract 2894 Poster Board II-870 Recent studies have identified TET2 and ASXL1 mutations in myeloid malignancies, suggesting that acquisition of these mutant alleles might precede the acquisition of JAK2 in some myeloproliferative neoplasm (MPN) patients. Moreover, the observation that JAK2 mutations are observed in minority of patients with leukemic transformation of JAK2-mutant MPNs suggests the possibility that JAK2 mutations are dispensable for leukemic transformation. However the role of TET2 and ASXL1 mutations in leukemic transformation has not been evaluated. We therefore investigated the mutational status of JAK2, TET2, and ASXL1 in 63 patients with leukemic transformation from a pre-existing MPN, including 49 unpaired secondary acute myeloid leukemia (sAML) samples and 14 patients for whom paired MPN and sAML samples were available. Mutations of TET2 and ASXL1 were found at a higher frequency in sAML samples transformed from MPNs than reported for sporadic MPNs (9/46 (19.6%) and 7/46 (15.2%), respectively). This was also higher than the mutational frequency of TET2 and ASXL1 in de novo AML (6.4% (3/47) and 4.3% (2/47), respectively) but similar to that of AML transformed from MDS (12.8% (5/39) and 15.4% (6/39)). All possible genetic combinations of JAK2, TET2, and ASXL1 status were observed in sAML patients. Analysis of paired samples reveal that TET2 mutations are far more likely to occur at leukemic transformation of MPN than at MPN diagnosis (p=0.013, Fisher's exact test) whereas ASXL1 mutations were equally likely to occur at MPN or sAML. Although mutations in JAK2 and in TET2 may not be retained at leukemic transformation from MPN, mutations in ASXL1 at MPN diagnosis were consistently retained at leukemic transformation. In addition, individual cases were observed where TET2 and/or ASXL1 mutations were found before acquisition of JAK2 mutations or clinical evidence of MPN, as well as cases where TET2 and ASXL1 mutations were acquired during leukemic transformation of a JAK2V617F-positive clone. These data suggest the mutational order of events in MPN and sAML pathogenesis might vary in different patients, and that TET2 and ASXL1 mutations might contribute in different patients to the development of MPN and/or to leukemic transformation. In addition, the identification of transformed AML cases with no evidence of pre-existing JAK2, TET2, and ASXL1 mutations indicates the existence of other, not yet identified, mutations necessary for leukemic transformation of MPNs. Disclosures: Levine: Novartis: Research Funding; TargeGen: Consultancy. Verstovsek:Incyte: ; Exelixis: ; Cephalon: ; SBIO: ; AstraZeneca: .

scholarly journals Combination approach to diagnosis and treatment of an elderly patient with chronic Ph-negative myeloproliferative neoplasm and concomitant surgical pathology. Clinical observation

MD-Onco ◽  
2021 ◽  
Vol 1 (1) ◽  
pp. 61-65
Author(s):  
Yu. E. Ryabukhina ◽  
P. A. Zeynalova ◽  
O. I. Timofeeva ◽  
F. M. Abbasbeyli ◽  
T. V. Ponomarev ◽  
...  
Keyword(s):  
Elderly Patient ◽  
Essential Thrombocythemia ◽  
Early Stage ◽  
Myeloproliferative Neoplasms ◽  
Myeloproliferative Neoplasm ◽  
Jak2 V617f ◽  
Primary Myelofibrosis ◽  
Left Femur ◽  
Hematopoietic Stem ◽  
Chronic Myeloproliferative Neoplasms

Chronic myeloproliferative neoplasms (CMPN), Ph-negative, are of clonal nature, develop on the level of hematopoietic stem cell and are characterized by proliferation of one or more hematopoietic pathways. Currently, the group of Ph-negative CMPN includes essential thrombocythemia, primary myelofibrosis, polycythemia vera, myeloproliferative neoplasm unclassifiable.Identification of mutations in the Jak2 (V617F), CALR, and MPL genes extended understanding of biological features of Ph-negative CMPN and improved differential diagnosis of myeloid neoplasms. Nonetheless, clinical practice still encounters difficulties in clear separation between such disorders as primary myelofibrosis, early-stage and transformation of essential thrombocythemia into myelofibrosis with high thrombocytosis. Thrombocytosis is one of the main risk factors for thromboembolic complications, especially in elderly people.A clinical case of an elderly patient with fracture of the left femur developed in the context of Ph-negative CMPN (myelofibrosis) with high level of thrombocytosis is presented which in combination with enforced long-term immobilization and presence of additional risk created danger of thrombosis and hemorrhage during surgery and in the postoperative period.

scholarly journals Aktualitások a primer myelofibrosis ellátásában

2016 ◽  
Vol 157 (39) ◽  
pp. 1547-1556
Author(s):  
Zsófia Simon ◽  
Imelda Marton ◽  
Zita Borbényi ◽  
Árpád Illés
Keyword(s):  
Treatment Approach ◽  
Myeloproliferative Neoplasms ◽  
Primary Myelofibrosis ◽  
Spleen Volume ◽  
Novel Therapy ◽  
Jak2 Inhibitor ◽  
Chronic Myeloproliferative Neoplasms ◽  
Associated Symptoms ◽  
Modifying Effect ◽  
Disease Modifying

Primary myelofibrosis is one of the Philadelphia negative chronic myeloproliferative neoplasms. It is a rare disease featured by cytopenias and hepatosplenomegaly. Although the etiology of the disease is still unknown, our knowledge about its pathology and prognosis has been improving in the last few years. Furthermore, the JAK2 inhibitor ruxolitinib has become available in Hungary since 2015. Beside its high efficacy in spleen volume and in reduction of myelofibrosis-associated symptoms, this novel therapy also exerts a disease-modifying effect and, therefore, ruxolitinib may improve the life expectancy too. Treatment approach of myelofibrosis has been changed these years, which gives a reason for this summary. Orv. Hetil., 2016, 157(39), 1547–1556.

JAK2 Inhibitor Therapy in Chronic Myeloproliferative Neoplasms Ph(-): Hematologic, Clinical and Molecular Responses

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 5059-5059
Author(s):  
Ana Esther Kerguelen Fuentes ◽  
Dolores Hernández-Maraver ◽  
Miguel Angel ◽  
Canales Albendea ◽  
Ana Rodriguez de la Rua
Keyword(s):  
Clinical Response ◽  
Conflicts Of Interest ◽  
Myeloproliferative Neoplasms ◽  
Molecular Response ◽  
Spleen Size ◽  
Molecular Responses ◽  
Allele Burden ◽  
Jak2 Inhibitor ◽  
Chronic Myeloproliferative Neoplasms ◽  
Jak2 Inhibitors

Abstract Abstract 5059 JAK2 inhibitors are known to improve symptoms, to control myeloproliferation and to reduce splenomegaly in patients diagnosed with chronic myeloproliferative neoplasms (MPNs)Ph(-). However their ability to decrease the allele burden and achieve molecular responses is controversial. Objective: To evaluate hematologic, clinical and molecular responses according to the criteria of the European LeukemiaNet and European Myelofibrosis Network in 13 patients treated with JAK2 inhibitors. Material and Methods: We performed a prospective study in the Haematology Service of the Hospital La Pazbetween 1987 and 2012 in 13 patients diagnosed with NMP Ph (-) and treated with of JAK2 inhibitors: 5 secondary mylofibrosis (SFM)to homozygous polycythemia vera JAK (+), 4 SFM to essential thrombocythemias JAK (-), 2 primary myelofibrosis (one JAK (-) and one heterozygous JAK (+)) and 2 homozygous PV JAK (+) resistant to hydrea. The RT-PCR was performed at 6 or 12 months after the first determination of the allelic burden. Median follow-up was 3 months (1 – 15). A) Hematologic Response (HR): 3/5 SFM to PV(1)/TE JAK(-)(2) reached HR at 3 months of initiation of JAK2 inhibitor to 20mg/day. Molecular and clinical response were not evaluated. B) Clinical Response: Three patients had a reduction in the spleen size. Only one patient in the SFM group had a reduction in the spleen size (18 cm before the drug was commenced to 13. 7 cm) and the allele burden decrease from 55% to 23% after 5 months of therapy with JAK2 inhibitor at 25mg/12h (increase of 5mg/12h after 15 days of initiation of medication). 2/3 MFS to TE JAK(-) had a reduction from 15, 3 cm before the drug was commenced to 9 cm after 3 months of therapy with JAK2 inhibitor at 20 mg/12h. 3/3 MFP JAK(-) had a 6cm reduction in spleen size. Twenty cm splenomegaly was documented before starting JAK2 inhibitor to 15 mg/day. C) Molecular Response: 2/5 SFM to PV decreased the previous allele burden value. One patient decreased by 25% the previous allele burden value (99. 28%) at 6 months of JAK2 inhibitor. Second patient decreased by 13% the previous allele burden value (55%) at 6 months of starting JAK2 inhibitor to 25 mg/day. In 1/2 PV, the previous allele burden value (93. 17%) decreased by 11. 4% at 6 months of starting JAK2 inhibitor at 100mg/24h. D) Lack of response and disease progression: One patient with SMF secondary to JAK 2 (-) ET had dose reductions from 20 mg twice a day secondary to grade IV thrombocytopenia and renal toxicity. Patient finally developed acute leukemia. Conclusions: Our study confirms that JAK2 inhibitors reduce splenomegaly in MPNs JAK(-)and JAK(+). Prospective studies with an adequate sample size are necessary to demonstrate whether splenomegaly and symptom reductions achieved with inhibition of JAK2 could be associated to decrease the allele burden and achieve molecular responses in MPNs JAK(+). Disclosures: No relevant conflicts of interest to declare.

scholarly journals Chronic myeloproliferative neoplasms and subsequent cancer risk: a Danish population-based cohort study

Blood ◽  
2011 ◽  
Vol 118 (25) ◽  
pp. 6515-6520 ◽  
Author(s):  
Henrik Frederiksen ◽  
Dóra Körmendiné Farkas ◽  
Christian Fynbo Christiansen ◽  
Hans Carl Hasselbalch ◽  
Henrik Toft Sørensen
Keyword(s):  
Cancer Risk ◽  
Myeloproliferative Neoplasms ◽  
Myeloproliferative Neoplasm ◽  
Hematologic Malignancies ◽  
Population Based ◽  
National Registry ◽  
Standardized Incidence Ratio ◽  
Chronic Myeloproliferative Neoplasms ◽  
Increased Risk ◽  
Subsequent Cancer

Abstract Patients with chronic myeloproliferative neoplasms, including essential thrombocythemia (ET), polycythemia vera (PV), and chronic myeloid leukemia (CML), are at increased risk of new hematologic malignancies, but their risk of nonhematologic malignancies remains unknown. In the present study, we assessed the risk of both types of malignancies after an ET, PV, or CML diagnosis. We linked 2 population-based nationwide registries, the Danish National Registry of Patients, covering all Danish hospitals and the Danish Cancer Registry, and assessed subsequent cancer risk in a cohort of all 7229 patients diagnosed with a chronic myeloproliferative neoplasm during 1977-2008. We compared the incidence of subsequent cancer in this cohort with that expected on the basis of cancer incidence in the general population (standardized incidence ratio). Overall, ET, PV, and CML patients were at increased risk of developing both new hematologic and nonhematologic cancers. The standardized incidence ratio for developing a nonhematologic cancer was 1.2 (95% confidence interval [95% CI]): 1.0-1.4) for patients with ET, 1.4 (95% CI: 1.3-1.5) for patients with PV, and 1.6 (95% CI: 1.3-2.0) for patients with CML. We conclude that patients with chronic myeloproliferative neoplasms are at increased risk of developing a new malignant disease.

scholarly journals Hydroxyurea-Induced Pneumopathy in a Patient With Myeloproliferative Syndrome

2018 ◽  
Vol 11 ◽  
pp. 117954761877068 ◽  
Author(s):  
Oriol Plans Galván ◽  
Hipólito Pérez Moltó ◽  
Ariadna Fabià-Mayans ◽  
Blanca Xicoy ◽  
José Luis Mate ◽  
...  
Keyword(s):  
Side Effects ◽  
Interstitial Pneumonitis ◽  
Myeloproliferative Neoplasms ◽  
Histological Study ◽  
Myeloproliferative Neoplasm ◽  
Skin Disorders ◽  
Respiratory Complications ◽  
Chronic Myeloproliferative Neoplasms ◽  
Myeloproliferative Syndrome

Hydroxyurea (HU) is a drug frequently used in the treatment of chronic myeloproliferative neoplasms. The most common side effects of this drug are pancytopenia, digestive and skin disorders. Respiratory complications are rare and there are less than 20 cases described, only 5 of which underwent an anatomopathological study. We present the case of a patient with chronic myeloproliferative neoplasm who developed interstitial pneumonitis probably due to HU according to histological study.

R723, a selective JAK2 inhibitor, effectively treats JAK2V617F-induced murine myeloproliferative neoplasm

Blood ◽  
2011 ◽  
Vol 117 (25) ◽  
pp. 6866-6875 ◽  
Author(s):  
Kotaro Shide ◽  
Takuro Kameda ◽  
Vadim Markovtsov ◽  
Haruko K. Shimoda ◽  
Elizabeth Tonkin ◽  
...  
Keyword(s):  
Mouse Model ◽  
Myeloproliferative Neoplasms ◽  
Myeloproliferative Neoplasm ◽  
Primary Myelofibrosis ◽  
Tumor Burden ◽  
Jak2 Inhibitor ◽  
Activating Mutations ◽  
Orally Bioavailable

Abstract The activating mutations in JAK2 (including JAK2V617F) that have been described in patients with myeloproliferative neoplasms (MPNs) are linked directly to MPN pathogenesis. We developed R723, an orally bioavailable small molecule that inhibits JAK2 activity in vitro by 50% at a concentration of 2nM, while having minimal effects on JAK3, TYK2, and JAK1 activity. R723 inhibited cytokine-independent CFU-E growth and constitutive activation of STAT5 in primary hematopoietic cells expressing JAK2V617F. In an anemia mouse model induced by phenylhydrazine, R723 inhibited erythropoiesis. In a leukemia mouse model using Ba/F3 cells expressing JAK2V617F, R723 treatment prolonged survival and decreased tumor burden. In V617F-transgenic mice that closely mimic human primary myelofibrosis, R723 treatment improved survival, hepatosplenomegaly, leukocytosis, and thrombocytosis. R723 preferentially targeted the JAK2-dependent pathway rather than the JAK1- and JAK3-dependent pathways in vivo, and its effects on T and B lymphocytes were mild compared with its effects on myeloid cells. Our preclinical data indicate that R723 has a favorable safety profile and the potential to become an efficacious treatment for patients with JAK2V617F-positive MPNs.

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