Myeloproliferative neoplasms 5 years after discovery of JAK2V617F: what is the impact of JAK2 inhibitor therapy?

2011 ◽  
Vol 52 (7) ◽  
pp. 1178-1187 ◽  
Author(s):  
Raoul Tibes ◽  
Ruben A. Mesa
Keyword(s):  
Myeloproliferative Neoplasms ◽  
Inhibitor Therapy ◽  
Jak2 Inhibitor ◽  
The Impact

Cytokine Profile Changes In 309 Myelofibrosis Patients: Comparison Of JAK1/JAK2 Inhibitor Therapy Vs. Placebo – Correlative Analysis From The Comfort-I Trial

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4074-4074 ◽  
Author(s):  
Amylou C. Dueck ◽  
Charles S. Cleeland ◽  
Robert Dantzer ◽  
Jeff Sloan ◽  
Srdan Verstovsek ◽  
...  
Keyword(s):  
Logistic Regression ◽  
Limit Of Detection ◽  
Inhibitor Therapy ◽  
Phase Iii ◽  
Jak2 Inhibitor ◽  
Combining Data ◽  
Cytokine Levels ◽  
The Impact ◽  
The Relationship ◽  
Over Time

Abstract Background Inflammatory deregulation may be a major factor in cancer related symptoms (Dantzer Nature Rev Clin Oncol 2012). Improved symptoms in myelofibrosis (MF) patients treated with single arm ruxolitinib (JAK1/JAK2 inhibitor) studies has been correlated with normalization of selected cytokines increased pre-therapy (c-reactive protein, IL-1ra, MIP-1b, TNF-a, and IL-6; Verstovsek NEJM 2010). We sought to assess the impact of JAK1/JAK2 inhibitor therapy on cytokine levels and the relationship between cytokine levels and symptoms prior to and during JAK1/JAK2 inhibitor therapy in the phase III placebo controlled COMFORT-I trial (Verstovsek NEJM 2012). Methods Cytokine levels (89 cytokines measured at baseline and at weeks 4 and 24) and MF symptoms (assessed by MFSAF 2.0 – Mesa JCO 2013) were collected during the blinded phase of COMFORT-I. Patients were randomized to ruxolitinib vs. placebo. Plasma was used for the measurement of cytokines using Rules-Based Medicine, Inc. (Austin, TX) Human MAP panel. Associations between the MFSAF total symptom score (TSS) and log2-transformed cytokine data were investigated at baseline using Spearman correlations and linear regression. Mixed models were used to assess cytokine and TSS changes over time within each arm and overall. Logistic regression was used to assess the relationship between baseline cytokines and TSS response (>/=50% reduction from baseline) at week 24, and between week 4 cytokine changes and TSS response (>/=50% reduction from baseline) at week 24 within each arm and overall. Mixed and logistic regression models combining data across arms also included terms for visit, arm, and visit-by-arm interaction. All models also included age, gender, and body mass index (BMI). Given the large number of cytokines being investigated, p<0.001 was considered statistically significant. Cytokine values below the limit of detection were set at the lowest limit of detection and 25 cytokines were excluded from statistical analysis due to having more than 30% of data missing or below the limit of detection. Results Patients: 309 subjects were randomized in COMFORT-I with median age 68 (range 40-91), 46% female, 50% primary myelofibrosis, and 61% high risk. All 309 subjects had cytokines measured at one or more of the three visits included in this analysis, with 308 having cytokine values paired with a TSS score at the same visit. Cytokines at Baseline: At baseline, the highest Spearman correlations with symptomatic burden (as assessed by the TSS) were observed for APOA1 (rho=-.21) and FERRITIN (rho=-.20), followed by INTLK5, MIP1A, MMP3, INTLK2, MGB, INTLK1A, and INTLK7 with correlations between -.15 and -.17 (all p<0.01). After adjusting for age, sex, and BMI, VCAM1 and APOA1 were significantly associated with TSS at baseline. Cytokine and Symptom changes during trial: Changing levels of 5 cytokines were significantly associated with change of TSS over time beyond the change due to visit, arm, visit-by-arm interaction, age, sex and BMI including VCAM1, LEPTIN, TIMP1, B2MICG, and TNFRII. Within the placebo arm, only 5 cytokines significantly changed over time compared to 46 cytokines in the ruxolitinib arm (visit-by-arm interaction was significant for 43 in the overall models). VCAM1, B2MICG, and TNFRII were among the 5 cytokines which changed in the placebo arm, and VCAM1, LEPTIN, TIMP1, B2MICG, and TNFRII were among the 46 cytokines which changed in the ruxolitinib arm. No baseline cytokines and no changes in cytokines at week 4 univariately predicted week 24 TSS response within either arm at the p<0.001 level. Conclusions In the first serial assessment of MF symptoms and plasma cytokine levels in the conduct of a placebo controlled trial we found 5 cytokines in which improved levels correlated with decreased MF symptom burden in ruxolitinib treated patients. Development of a multivariate model for predicting symptom response, correlations with splenic response and impact on survival benefit of therapy is ongoing. Disclosures: No relevant conflicts of interest to declare.

The JAK2V617F Oncogene, Associated with Myeloproliferative Neoplasms, Requires Expression of Inducible Phosphofructokinase/Fructose Bisphosphatase 3 for Cell Growth and Increased Metabolic Activity

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 793-793
Author(s):  
Mamatha M Reddy ◽  
Margret Fernandes ◽  
James D. Griffin ◽  
Martin Sattler
Keyword(s):  
Cell Growth ◽  
Glucose Uptake ◽  
Metabolic Activity ◽  
Glucose Transporter ◽  
Conflicts Of Interest ◽  
Myeloproliferative Neoplasms ◽  
Cell Surface Expression ◽  
Jak2 Inhibitor ◽  
Hel Cells ◽  
The Impact

Abstract Abstract 793 Myeloproliferative neoplasms (MPNs) and myeloid leukemias, characterized by overproduction of myeloid lineage cells, are frequently associated with transforming oncogenic kinases, including JAK2V617F, BCR-ABL, or FLT3-ITD. The mechanisms that regulate altered energy metabolism in these diseases are poorly understood but cancer cells tend to produce energy through increased glycolysis instead of oxidative phosphorylation, even under normoxic conditions (Warburg effect). Our data in JAK2V617F-transformed HEL cells show that glucose uptake, the first step in glucose metabolism, is reduced in response to a JAK2 inhibitor (−22.29%, p<0.05, n=3). Further, introduction of JAK2V617F into murine BaF3 cells resulted in increased glucose uptake (103.72%, p<0.05, n=3), compared to parental BaF3 cells. Exposure of cells transformed by BCR/ABL or FLT3-ITD with appropriate kinase inhibitors similarly resulted in a 30 to 40% decrease in glucose uptake, and introduction of either BCR-ABL or FLT3-ITD into BaF3 cells resulted in substantial increases in glucose uptake (BCR-ABL, +122.74%, and FLT3-ITD, +142.77%; p<0.05, n=3). Consistent with an increase in glucose uptake, we also found elevated cell surface expression of the glucose transporter Glut1 in BaF3.JAK2V617F cells. Importantly, cell growth and metabolic activity were strictly dependent on the presence of glucose in the culture medium. Also, treatment with the hexokinase inhibitor, 2-deoxyglucose, led to reduced cell growth, further supporting the notion that JAK2V617F transformed cells rely on glucose for their metabolic functions. JAK2V617F increased the expression of at least two rate-limiting enzymes in the glycolytic pathway, including hexokinase 2 (HK2) as well as 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) and in particular, a JAK2 inhibitor substantially decreased the expression of PFKFB3 in HEL cells. To determine the significance of altered PFKFB3 expression, we targeted PFKFB3 in HEL cells using a lentiviral-based shRNA approach. We found that PFKFB3 knockdown reduced cell growth by 46.3 to 46.8% in HEL cells (p<0.05, n=3) compared to control shRNA. The impact on cell growth was similar under normoxic (20% O2) compared to hypoxic (0.1% O2) conditions (−58.2% to −45.5%; p<0.05, n=3), further underlining the importance of this pathway for cell growth. We also observed a reduction in oxidative metabolic activity (−32.26% to −34.14%, p<0.05, n=3) and glucose uptake (−28.58% to −22.5%, p<0.05, n=3) in response to PFKFB3 knockdown. Finally, in order to understand the role of the JAK2V617F target STAT5 in the regulation of increased PFKFB3 expression, we used BaF3 cells with a doxycycline inducible form of active STAT5. These cells, upon induction of active STAT5, showed increased growth and metabolic activity as well as elevated expression of PFKFB3, compared to controls. It is not known whether PFKFB3 is a direct transcriptional target of STAT5. Overall, these data suggest that inducible PFKFB3 is required for increased growth, metabolic activity and is regulated through the JAK2V617F/STAT5 pathway, hinting at novel targets for drug development. Small molecule drugs that target PFKFB3 would be expected to specifically inhibit this pathway and to have activity in diseases dependent on JAK2V617F or active STAT5 in related malignancies. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Efficacy of the JAK2 inhibitor INCB16562 in a murine model of MPLW515L-induced thrombocytosis and myelofibrosis

Blood ◽  
2010 ◽  
Vol 115 (14) ◽  
pp. 2919-2927 ◽  
Author(s):  
Priya Koppikar ◽  
Omar Abdel-Wahab ◽  
Cyrus Hedvat ◽  
Sachie Marubayashi ◽  
Jay Patel ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Kinase Inhibitors ◽  
Myeloproliferative Neoplasms ◽  
Inhibitor Therapy ◽  
Murine Bone Marrow ◽  
Jak2 Inhibitor ◽  
Cell Counts ◽  
Vehicle Treatment

Abstract The discovery of JAK2 and MPL mutations in patients with myeloproliferative neoplasms (MPNs) provided important insight into the genetic basis of these disorders and led to the development of JAK2 kinase inhibitors for MPN therapy. Although recent studies have shown that JAK2 kinase inhibitors demonstrate efficacy in a JAK2V617F murine bone marrow transplantation model, the effects of JAK2 inhibitors on MPLW515L-mediated myeloproliferation have not been investigated. In this report, we describe the in vitro and in vivo effects of INCB16562, a small-molecule JAK2 inhibitor. INCB16562 inhibited proliferation and signaling in cell lines transformed by JAK2 and MPL mutations. Compared with vehicle treatment, INCB16562 treatment improved survival, normalized white blood cell counts and platelet counts, and markedly reduced extramedullary hematopoeisis and bone marrow fibrosis. We observed inhibition of STAT3 and STAT5 phosphorylation in vivo consistent with potent inhibition of JAK-STAT signaling. These data suggest JAK2 inhibitor therapy may be of value in the treatment of JAK2V617F-negative MPNs. However, we did not observe a decrease in the size of the malignant clone in the bone marrow of treated mice at the end of therapy, which suggests that JAK2 inhibitor therapy, by itself, was not curative in this MPN model.

Living with an MPN in Ireland: patients' and caregivers' perspectives

2021 ◽  
Vol 30 (17) ◽  
pp. S24-S30
Author(s):  
Geraldine Walpole ◽  
Mary Kelly ◽  
Joy Lewis ◽  
Avril Gleeson ◽  
Ann-Marie Cullen ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Unmet Needs ◽  
Negative Impact ◽  
Peer Group ◽  
Myeloproliferative Neoplasms ◽  
Symptom Burden ◽  
Emotional Wellbeing ◽  
The Republic ◽  
The Impact

Myeloproliferative neoplasms (MPNs) are associated with a high disease burden, reduced quality of life and shortened survival. The aim of this questionnaire was to gain patients' and caregivers' perspectives on the impact of living with an MPN in the Republic of Ireland. An Irish adaptation of the ‘Global MPN Landmark survey’ was conducted. Fifty-one patients and 44 caregivers completed the questionnaire. Patients reported a wide variety of symptoms at the time of questionnaire completion; fatigue, bone pain and pruritus being most frequently reported. Approximately one-third of respondents from each of the groups (patients and caregivers) reported a negative impact of MPNs on their emotional wellbeing and daily lives. The study findings revealed that, despite treatment, symptom burden remains high, and several unmet needs exist, including educational, emotional and peer group support. Interventions that focus on reducing symptom burden and addressing these unmet needs, may improve the quality of life for patients with MPNs and their caregivers.

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.

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