Chronic myeloproliferative neoplasms (MPNs) are a group of related conditions characterized by the overproduction of cells from one or more myeloid lineages. More than 95% of cases of polycythemia ...vera, and roughly half of essential thrombocythemia and primary myelofibrosis acquire a unique somatic 1849G>T JAK2 mutation (encoding V617F) that is believed to be a critical driver of excess proliferation. We report here that JAK2V617F-associated disease is strongly associated with a specific constitutional JAK2 haplotype, designated 46/1, in all three disease entities compared to healthy controls (polycythemia vera, n = 192, P = 2.9 × 10−16; essential thrombocythemia, n = 78, P = 8.2 × 10−9 and myelofibrosis, n = 41, P = 8.0 × 10−5). Furthermore, JAK2V617F specifically arises on the 46/1 allele in most cases. The 46/1 JAK2 haplotype thus predisposes to the development of JAK2V617F-associated MPNs (OR = 3.7; 95% CI = 3.1-4.3) and provides a model whereby a constitutional genetic factor is associated with an increased risk of acquiring a specific somatic mutation.
The major weakness of most knock-in JAK2V617F mouse models is the presence of the JAK2 mutation in all rather than in a few hematopoietic stem cells (HSC), such as in human “early-stage” ...myeloproliferative neoplasms (MPN). Understanding the mechanisms of disease initiation is critical as underscored by the incidence of clonal hematopoiesis of indeterminate potential associated with JAK2V617F. Currently, such studies require competitive transplantation. Here, we report a mouse model obtained by crossing JAK2V617F/WT knock-in mice with PF4iCre transgenic mice. As expected, PF4iCre;JAK2V617F/WT mice developed an early thrombocytosis resulting from the expression of JAK2V617F in the megakaryocytes. However, these mice then developed a polycythemia vera–like phenotype at 10 weeks of age. Using mT/mG reporter mice, we demonstrated that Cre recombination was present in all hematopoietic compartments, including in a low number of HSC. The frequency of mutated cells increased along hematopoietic differentiation mimicking the clonal expansion observed in essential thrombocythemia and polycythemia vera patients. This model thus mimics the HSC compartment observed in early-stage MPN, with a small number of JAK2V617F HSC competing with a majority of JAK2WT HSC. PF4iCre;JAK2V617F/WT mice are a promising tool to investigate the mechanisms that regulate clonal dominance and progression to myelofibrosis.
•PF4iCre;JAK2V617F/WT mice develop a full MPN that mimics polycythemia vera.•The PF4iCre system induces JAK2V617F mutation in a small subset of HSC.
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Objectives
Population‐based studies have reported an increased incidence of skin cancer in patients with essential thrombocythemia (ET) and polycythemia vera (PV). We have examined the risk factors ...for non‐melanoma skin cancer (NMSC) in patients diagnosed with ET or PV during 1973–2012.
Methods
A case–control study was performed to compare the clinical and treatment‐related data of 51 ET/PV patients who had NMSC with that of 401 patients who did not. We also evaluated whether polymorphisms in 12 genes involved in DNA integrity predisposed to NMSC.
Results
By multivariate logistic regression analysis, risk factors for NMSC were older age (OR: 1.7, 95% CI: 1.3–2.1, P < 0.001), male sex (OR: 2.1, 95% CI: 1.1–3.8, P = 0.023), higher cumulated hydroxycarbamide dose (OR: 1.3, 95% CI: 1.1–1.7, P = 0.017), and busulphan exposure (OR: 3.2, 95% CI: 1.05–10.0, P = 0.041). On the time‐to‐event prognostic model, factors independently associated with increased cumulative incidence of NMSC were age (5% increased risk per year; P < 0.001), male sex (91% increased risk; P = 0.022), and hydroxycarbamide exposure (22% increased risk; P = 0.065). No susceptibility gene variant was identified.
Conclusions
These findings suggest that the risk to develop NMSC in ET/PV patients results from the combined effect of common risk factors (age, male sex) together with cytoreductive treatment.
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•Water resistant CMC-PVA films were developed using citric acid as a cross linker.•Functional property of the film was improved by incorporation of Aloe vera gel.•Addition of citric ...acid improved the mechanical properties of the film.•Demonstrated shelf life extension of meat in active crosslinked film.
The potential of citric acid (CA) included as a crosslinker for development of CMC-PVA films with better mechanical and lower solubility was examined. To make functional active packaging films for storage of perishable food products, the role of Aloe vera (AV) was also investigated. Addition of CA effectively improved the mechanical properties, reduced the water solubility, moisture content and water vapour permeability of the film. FTIR analysis confirmed that incorporation of CA led to formation of ester bonds and hence cross linking. AV the active component of the composite film, didn’t interfere with the barrier properties of the film and served as a protector against UV light. The film delayed lipid peroxidation and microbial growth of packaged minced chicken meat. Thus, incorporation of CA and AV were efficacious in developing an eco-friendly, water-resistant active packaging film that extended the shelf-life of minced meat.
Highlights • IFNα made ET with JAK2V617F+ have better hematologic response than JAK2V617F−. • For PV patients with JAK2V617F+ , IFN gained better molecular response than HU. • ET patients with ...JAK2V617F+ demonstrated a definite advantage in PFS. • For PV patients with JAK2V617F+ , IFN α-2b was superior to HU in PFS. • IFN improved vasomotor symptoms, especially distal paresthesias and erythromelalgia.
Calreticulin (CALR) mutations have been reported in Janus kinase 2 (JAK2)– and myeloproliferative leukemia (MPL)–negative essential thrombocythemia and primary myelofibrosis. In contrast, no CALR ...mutations have ever been reported in the context of polycythemia vera (PV). Here, we describe 2 JAK2V617F-JAK2exon12–negative PV patients who presented with a CALR mutation in peripheral granulocytes at the time of diagnosis. In both cases, the CALR mutation was a 52-bp deletion. Single burst-forming units–erythroid (BFU-E) from 1 patient were grown in vitro and genotyped: the same CALR del 52-bp mutation was noted in 31 of the 37 colonies examined; 30 of 31 BFU-E were heterozygous for CALR del 52 bp, and 1 of 31 BFU-E was homozygous for CALR del 52 bp. In summary, although unknown mutations leading to PV cannot be ruled out, our results suggest that CALR mutations can be associated with JAK2-negative PV.
•Major CALR-mutated clones may be observed in polycythemia vera negative for JAK2 mutations.
Objective: To define the clinicopathologic features, outcome, and prognostic indicators of myelofibrosis (MF) in Asian patients.
Methods: Two hundred and seventy consecutive Chinese patients (primary ...MF, n = 207; post-polycythemia vera MF, n = 27; and post-essential thrombocythemia MF, n = 36) from seven regional referral hospitals were analyzed.
Results: The median overall survival (OS) for primary MF was 66 months. Multivariate analysis showed that age >65 years (P = 0.02), platelet count <100 × 10
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/l (P = 0.001), and leukemic transformation (P = 0.001) negatively impacted on OS. The median OS of 63 patients with secondary MF was 44 months. In primary MF, the 10-year cumulative risk of leukemic transformation was 28%. On multivariate analysis, unfavorable karyotypes significantly predicted inferior leukemia-free survival (LFS) (P = 0.03). In secondary MF, the 10-year cumulative risk of leukemic transformation was 31%. Circulating blasts ≥1% significantly predicted inferior LFS (P = 0.04). The international prognostic scoring system (IPSS) and dynamic IPSS were not significant survival predictors in our cohort. Eighteen patients underwent allogeneic hematopoietic stem cell transplantation. The median OS post-transplantation was merely 19 months.
Discussion: Platelet count <100 × 10
9
/l, unfavorable karyotypes, and circulating blasts >1% were negative prognostic indicators.
Conclusion: Chinese MF patients were similar to Western patients in clinicopathologic features and outcome.
Therapeutic erythrocytapheresis (TE) is a more efficient strategy compared to phlebotomy to deplete levels of haematocrit in primary and secondary erythrocytosis.
To analyse response rate and safety ...profile of TE in polycythemia vera (PV) and secondary erythrocytosis (SE).
Retrospective review of all patients with PV or SE treated with TE, due to phlebotomy failure, or comorbidities that prevented changes of blood volumen.
217 TE sessions (48 PV and 79 SE) corresponding to 20 patients (12 ES and 8 PV). Response were achieved in 87.5% of PV patients and in 50% of SE patients. Adverse effects related to TE performance occurred in 7.08%.
Despite our small sample size and the heterogeneous nature of the patients included, we can postulate that TE is a secure strategy that can achieve haematocrit depletion in a shorter time than phlebotomy, specifically in PV patients and in selected cases of SE with expected haemodynamic intolerance to phlebotomies or in patients who fail to respond to phlebotomies.
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