Glucose-6-phosphate dehydrogenase deficiency reduces susceptibility to cancer of endodermal origin.

Background: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common inherited enzyme defect worldwide. There is a growing scientific evidence for a protective role of G6PD deficiency against carcinogenesis. In this retrospective analysis, we tested the hypothesis that G6PD deficiency may reduce the risk of developing cancer in a tissue-specific manner. Material and methods: The study was conducted using data from 11,708 subjects undergoing gastrointestinal endoscopic procedures between 2002 and 2018 and tested for G6PD status in a teaching hospital of Northern Sardinia, Italy. Results: A 40% reduction of risk for cancer of endodermal origin was observed among G6PD-deficient patients compared with subjects with normal enzyme activity (relative risk (RR) 0.61, 95% confidence interval (CI) 0.47-0.80) in both genders, confirmed by multivariable generalized linear regression after adjusting for age, sex, smoking habits, body mass index, diabetes and socio-economic status. The 'protective' effect of G6PD deficiency was larger for gastric cancer (RR 0.41, 95% CI 0.18-0.99), hepatocellular carcinoma (RR 0.48, 95% CI 0.26-0.92) and colorectal cancer (RR 0.72, 95% CI 0.53-0.98), while a non-significant risk was observed for breast, prostate, lung, hematopoietic and metastases (primary site unknown). Conclusions: Our results suggest a reduced susceptibility to develop cancers, mostly of endodermal origin (stomach, colon and liver), but not of ectodermal/mesodermal origin, in carriers of G6PD deficiency. The effects of G6PD deficiency on carcinogenesis need further studies to better understand how cancer cells originating from different germ layers use pentose phosphate pathway to proliferate.

Analysis of JAK2V617F mutation in Jordanian patients with myeloproliferative neoplasms.

OBJECTIVE/BACKGROUND: Myeloproliferative neoplasms (MPNs) are heterogeneous clonal bone marrow stem cell disorders and include polycythemia vera (PV), essential thrombocythemia (ET), and idiopathic myelofibrosis (IMF) neoplasia. In 2005, the JAK2(V617F) mutation was identified in Philadelphia chromosome-negative patients. The aim of this study was to sequence coding exons 12 and 14 of the JAK2 gene in Jordanian patients with MPN. METHODS: Both exons 12 and 14 of the JAK2 gene were amplified using polymerase chain reaction from DNA extracted from 68 blood and bone marrow samples belonging to 57 MPN patients and subjected to DNA sequencing. RESULTS: JAK2(V617F) mutations were detected in 26 of 57 Jordanian patients (45%) with different MPNs. JAK2(V617F) was identified in 70%, 31%, and 14% of PV, ET, and IMF cases, respectively. Five men diagnosed with PV were homozygous for JAK2(V617F), whereas the other 21 patients were heterozygous for the mutation. Neither the JAK2(V617F) mutation nor any DNA polymorphism in exon 12 or exon 14 of the JAK2 gene was detected among the 40 leukemic patients. A rare single nucleotide polymorphism, c.1860C→T (rs375442615), was detected in one patient with ET. CONCLUSION: This study is the first molecular investigation of the JAK2 gene in Jordan. We successfully identified the JAK2(V617F) mutation in Jordanian patients with Philadelphia chromosome-negative MPNs. Our results provide a basis for the early detection of this mutation and simplify the diagnostic workup for these disorders at the molecular level.

The JAK2 46/1 haplotype (GGCC) in myeloproliferative neoplasms and splanchnic vein thrombosis: a pooled analysis of 26 observational studies.

Numbers of observational studies suggest that the JAK2 46/1 (GGCC) haplotype may increase the risk of myeloproliferative neoplasms (MPNs) and splanchnic vein thrombosis (SVT), but the results remain controversial. We aimed to examine the association between the JAK2 46/1 haplotype and risk of MPNs and SVT by conducting a meta-analysis. PubMed, EMBASE, Cochrane Library, CBM, and CNKI databases were searched to identify eligible studies without restrictions and by reviewing reference lists of obtained articles. Both fixed and random-effects models were used to calculate the summary risk estimates. We identified 26 observational studies of the JAK2 46/1 haplotype and risk of MPNs and SVT involving 8,561 cases and 7,434 participants. In the overall analysis, it was found that the JAK2 46/1 haplotype significantly elevated the risk of MPNs (rs10974944: C vs T: odds ratio (OR) = 2.19, 95 % confidence interval (CI) = 1.86-2.57, P < 0.0001; CC vs TT: OR = 4.63, 95 % CI = 3.32-6.47, P < 0.0001; CT vs TT: OR = 2.49, 95 % CI = 2.11-2.95, P < 0.0001; (CC + CT) vs TT: OR = 2.92, 95 % CI = 2.51-3.39, P < 0.0001; rs12343867: C vs T: OR = 1.88, 95 % CI = 1.59-2.22, P < 0.0001; CC vs TT: OR = 3.16, 95 %CI = 2.14-4.65, P < 0.0001; CT vs TT: OR = 2.04, 95 % CI = 1.51-2.74, P < 0.0001; (CC + CT) vs TT: OR = 2.25, 95 % CI = 1.73-2.95, P < 0.0001) and SVT (C vs T: OR = 1.27, 95 % CI = 1.06-1.52, P = 0.011; CC vs TT: OR = 2.33, 95 % CI = 1.42-3.81, P = 0.001; (CC + CT) vs TT: OR = 1.25, 95 % CI = 1.02-1.53, P = 0.034). There was no evidence of a significant association between the rs12343867 and the risk of SVT in the genetic model (CT vs TT: OR = 1.01, 95 % CI = 0.80-1.29, P = 0.906). This meta-analysis provides new evidence supporting the conclusion that the JAK2 46/1 haplotype enrichment is significantly associated with the development of MPNs and SVT in these patients.

Human fucosyltransferase 6 enables prostate cancer metastasis to bone.

BACKGROUND: The interaction between human prostate cancer (PCa) cells and bone marrow (BM) endothelium follows a rolling-and-adhesion cascade mediated by E-selectin ligand (ESL): E-selectin. This adhesion is enabled by elevated expression of α-1,3-fucosyltransferases (FTs), enzymes responsible for ESL-mediated bone metastasis in humans. In contrast, the incidence of bone metastasis in mice is rare. METHODS: FT 3, 6 and 7 were overexpressed in mouse PCa cells. The rolling cell number, cell-rolling velocity and transendothelial migration were characterised in vitro. Fucosyltransferases-transduced mouse PCa cells expressing luciferase were inoculated into mice via left ventricle to compare the capability of bone metastasis. Mass spectrometry and immunoprecipitation were utilised for identification of ESLs. RESULTS: Overexpression of FT3, FT6 or FT7 restored ESLs and enabled mouse PCa cells to roll and adhere in E-selectin-functionalised microtubes, similar to trafficking of circulating PCa cells in BM vessels. Following intracardiac inoculation, FT6-transduced cells induced robust bone metastasis in mice. Inhibition of FT6 by a fucose mimetic significantly reduced bone metastasis. Importantly, comparison of FT3, FT6 and FT7 gene expression in existing clinical samples showed significant upregulation of FT6 in PCa-distant metastases. CONCLUSION: FT6 is a key mediator of PCa cells trafficking to the BM. It may serve as a viable drug target in preclinical tests of therapeutics for reduction of PCa bone metastasis.

Th-MYCN mice with caspase-8 deficiency develop advanced neuroblastoma with bone marrow metastasis.

Neuroblastoma, the most common extracranial pediatric solid tumor, is responsible for 15% of all childhood cancer deaths. Patients frequently present at diagnosis with metastatic disease, particularly to the bone marrow. Advances in therapy and understanding of the metastatic process have been limited due, in part, to the lack of animal models harboring bone marrow disease. The widely used transgenic model, the Th-MYCN mouse, exhibits limited metastasis to this site. Here, we establish the first genetic immunocompetent mouse model for metastatic neuroblastoma with enhanced secondary tumors in the bone marrow. This model recapitulates 2 frequent alterations in metastatic neuroblastoma, overexpression of MYCN and loss of caspase-8 expression. Mouse caspase-8 gene was deleted in neural crest lineage cells by crossing a Th-Cre transgenic mouse with a caspase-8 conditional knockout mouse. This mouse was then crossed with the neuroblastoma prone Th-MYCN mouse. Although overexpression of MYCN by itself rarely caused bone marrow metastasis, combining MYCN overexpression and caspase-8 deletion significantly enhanced bone marrow metastasis (37% incidence). Microarray expression studies of the primary tumors mRNAs and microRNAs revealed extracellular matrix structural changes, increased expression of genes involved in epithelial to mesenchymal transition, inflammation, and downregulation of miR-7a and miR-29b. These molecular changes have been shown to be associated with tumor progression and activation of the cytokine TGF-ß pathway in various tumor models. Cytokine TGF-ß can preferentially promote single cell motility and blood-borne metastasis and therefore activation of this pathway may explain the enhanced bone marrow metastasis observed in this animal model.

Pure curcumin increases the expression of SOCS1 and SOCS3 in myeloproliferative neoplasms through suppressing class I histone deacetylases.

Suppressors of cytokine signaling, SOCS1 and SOCS3, are important negative regulators of Janus kinase 2/signal transducers and activators of transcription signaling, which is constitutively activated in myeloproliferative neoplasms (MPNs) and leukemia. Curcumin has been shown to possess anticancer activity through different mechanisms. However, whether curcumin can regulate the expression of SOCS1 and SOCS3 is still unknown. Here, we found that curcumin elevated the expression of SOCS1 and SOCS3 via triggering acetylation of histone in the regions of SOCS1 and SOCS3 promoter in K562 and HEL cells. As a novel histone deacetylases (HDACs) inhibitor, curcumin inhibited HDAC enzyme activities and decreased the levels of HDAC1, 3 and 8 but not HDAC2. Knockdown of HDAC8 by small interfering RNA markedly elevated the expression of SOCS1 and SOCS3. Moreover, ectopic expression of HDAC8 decreased the levels of SOCS1 and SOCS3. Thus, HDAC8 plays an important role in the modulation of SOCS1 and SOCS3 by curcumin. Also, trichostatin A (TSA), an inhibitor of HDACs, increased the levels of SOCS1 and SOCS3. Furthermore, curcumin increased the transcript levels of SOCS1 and SOCS3 and significantly inhibited the clonogenic activity of hematopoietic progenitors from patients with MPNs. Finally, curcumin markedly inhibited HDAC activities and decreased HDAC8 levels in primary MPN cells. Taken together, our data uncover a regulatory mechanism of SOCS1 and SOCS3 through inhibition of HDAC activity (especially HDAC8) by curcumin. Thus, being a relative non-toxic agent, curcumin may offer a therapeutic advantage in the clinical treatment for MPNs.

Diagnostic value of JAK2 V617F somatic mutation for myeloproliferative cancer in 49 488 individuals from the general population.

The JAK2 V617F somatic mutation is present in the majority of patients with myeloproliferative cancer (polycythaemia vera, essential thrombocytosis, and primary myelofibrosis). However, the diagnostic value of the JAK2 V617F somatic mutation for myeloproliferative cancer in the general population is unknown. We examined this question in 49 488 individuals from the Copenhagen General Population Study. We also examined the association between JAK2 V617F somatic mutation, rs10974944 germline genotype, haematological phenotype, any cancer, haematological cancer, myeloproliferative cancer, ischaemic heart disease, and venous thromboembolism. The JAK2 V617F somatic mutation was present in 0·1% (n = 68), increasing across rs10974944 germline genotypes (P-trend = 0·001). JAK2 V617F somatic mutation positives versus negatives had higher erythrocyte (P = 2 × 10(-5) ), thrombocyte (P = 2 × 10(-16) ), and leucocyte (P = 4 × 10(-9) ) counts, and had 2·7-/2·5-fold risk of cancer (prevalent/incident), 44-/28-fold risk of haematological cancer, 221-/97-fold risk of myeloproliferative cancer, 2·2-/1·2-fold risk of ischaemic heart disease, and 3·1-/1·0-fold risk of venous thromboembolism. By combining conventional haematological parameters with a test for the JAK2 V617F somatic mutation, myelo;?>proliferative cancer could be identified or ruled out with a sensitivity of 47-100% and a specificity of 98-100%. In conclusion, in the general population the JAK2 V617F somatic mutation has a high diagnostic value for myeloproliferative cancer when combined with conventional haematological parameters.

Molecular diagnosis of the myeloproliferative neoplasms: UK guidelines for the detection of JAK2 V617F and other relevant mutations.

Molecular genetic assays for the detection of the JAK2 V617F (c.1849G>T) and other pathogenetic mutations within JAK2 exon 12 and MPL exon 10 are part of the routine diagnostic workup for patients presenting with erythrocytosis, thrombocytosis or otherwise suspected to have a myeloproliferative neoplasm. A wide choice of techniques are available for the detection of these mutations, leading to potential difficulties for clinical laboratories in deciding upon the most appropriate assay, which can lead to problems with inter-laboratory standardization. Here, we discuss the most important issues for a clinical diagnostic laboratory in choosing a technique, particularly for detection of the JAK2 V617F mutation at diagnosis. The JAK2 V617F detection assay should be both specific and sensitive enough to detect a mutant allele burden as low as 1-3%. Indeed, the use of sensitive assays increases the detection rate of the JAK2 V617F mutation within myeloproliferative neoplasms. Given their diagnostic relevance, it is also beneficial and relatively straightforward to screen JAK2 V617F negative patients for JAK2 exon 12 mutations (in the case of erythrocytosis) or MPL exon 10 mutations (thrombocytosis or myelofibrosis) using appropriate assays. Molecular results should be considered in the context of clinical findings and other haematological or laboratory results.

[Portal vein thrombosis as the main symptom of unclassified JAK2-positive myeloproliferative neoplasm--case report]. / Zakrzepica ukladu wrotnego jako glówny objaw niesklasyfikowanego JAK2-dodatniego nowotworu mieloproliferacyjnego--opis przypadku.

We report a case of a patient with a diagnosis of myeloproliferative neoplasm, unclassifiable, manifested only portal vein thrombosis and followed by cirrhosis of the liver. 37-year-old patient, previously healthy, without congenital thrombophilia, without prior thrombosis, with normal peripheral blood morphology were signs of extensive portal vein system, with massive collateral circulation. Patient did not meet the criteria for diagnosis of any of the classic myeloproliferative neoplasms. Bone marrow examination revealed hyperplasia and presence of single polymorphic megakaryocytes. Positive JAK2V617F mutation status was typical for myeloproliferative neoplasm. Therefore, that the portal system thrombosis is, sometimes accompanying symptom of other myeloproliferative neoplasm, caused by mutations, including polycythemia vera, essential thrombocythaemia and primary myelofibrisis, one can assume that between this mutation and observed in this patient thrombosis is relationship, despite the absence of changes in peripheral blood. This may suggest that we are dealing with myeloproliferative neoplasm, in which platelets are indeed produced in normal numbers, but they are functionally activated, causing disturbances apparently unusual for cancer. This requires confirmation in further studies.

The decrease in prolidase activity in myeloproliferative neoplasms.

BACKGROUND: The development of bone marrow fibrosis is a severe complication in hematological diseases. The progress of bone marrow myelofibrosis is evaluated by a trephine examination and may be characterized by the biochemical markers of collagen turnover determination. OBJECTIVES: Investigation of serum prolidase activity and biochemical markers of collagen metabolism in order to establish its role in the development of bone marrow fibrosis. MATERIAL AND METHODS: The group of 37 patients with myeloproliferative neoplasms (MPN) before treatment, consisted of 16 patients with chronic myeloid leukemia (CML), 7 with primary myelofibrosis (PMF), 8 with essential thrombocythopenia (ET), and 6 with polycythemia vera (PV). RESULTS: It was found that the plasma activity of prolidase (Pro) was reduced to almost half together with the serum level of osteocalcin (BGL), and hydroxyproline (H-PRO) in the serum and urine of patients with MPN in comparison to the control group. In the MPN group of patients, the levels of N-terminal procollagen III peptide (PIIINP), type I procollagen (PICP) and the C-terminal telopeptide of type I collagen (ICTP) were significantly higher. CONCLUSIONS: The alteration of collagen turnover markers in the MPN patient group (the elevation of synthesis and inhibition of collagen catabolism rate) has suggested that a diminished prolidase activity may contribute to such alteration of collagen metabolism and should be consider a biomarker of MPN progress.

Genetic and epigenetic complexity in myeloproliferative neoplasms.

The past 7 years have witnessed remarkable progress in our understanding of the genetics of BCR-ABL-negative myeloproliferative neoplasms (MPNs) and has revealed layers of unexpected complexity. Deregulation of JAK2 signaling has emerged as a central feature, but despite having biological activities that recapitulate the cardinal features MPNs in model systems, JAK2 mutations are often secondary events. Several other mutated genes have been identified with a common theme of involvement in the epigenetic control of gene expression. Remarkably, the somatic mutations identified to date do not seem to be acquired in any preferred order, and it is possible that the disease-initiating events remain to be identified. The finding of complex clonal hierarchies in many cases suggests genetic instability that, in principle, may be inherited or acquired. A common haplotype has been identified that is strongly associated with the acquisition of JAK2 mutations, but the cause of relatively high-penetrance familial predisposition to MPNs remains elusive. This review summarizes the established facts relating to the genetics of MPNs, but highlights recent findings and areas of controversy.

JAK2 inhibitors: are they the solution?

The discovery of the JAK2V617F mutation in patients with Philadelphia-negative myeloproliferative neoplasms (Ph-negative MPN) started the era of targeted therapy for these diseases. Until now, patients had few treatment options available, which usually were restricted to hydroxyurea, interferon preparations, and chemotherapy in more aggressive cases. JAK2 inhibitors have been developed over the past 5 years, and the results of the first clinical trials with JAK2 inhibitors for patients with myelofibrosis were recently published. Current research results suggest that JAK2 inhibitors have a potential to decrease disease burden and its activity, as manifested by a decrease in splenomegaly and improvement in systemic disease-related symptoms, but they do not seem to be able to eradicate the malignant clone. However, JAK2 inhibitors help patients regardless of their mutation status, because patients without JAK2V617F mutation benefit to the same extent as patients with JAK2V617F mutation. A greater understanding of the pathophysiology of MPNs is needed before we can cure myelofibrosis with drug therapy. Currently, several new JAK2 inhibitors are in clinical trials for patients with myelofibrosis, and clinical trials for patients with polycythemia vera and essential thrombocythemia have also started. We review recent data on JAK2 inhibitors for the management of patients with Ph-negative MPNs.

JAK2 V617F-dependent upregulation of PU.1 expression in the peripheral blood of myeloproliferative neoplasm patients.

Myeloproliferative neoplasms (MPN) are multiple disease entities characterized by clonal expansion of one or more of the myeloid lineages (i.e. granulocytic, erythroid, megakaryocytic and mast cell). JAK2 mutations, such as the common V617F substitution and the less common exon 12 mutations, are frequently detected in such tumor cells and have been incorporated into the diagnostic criteria published by the World Health Organization since 2008. However, the mechanism by which these mutations contribute to MPN development is poorly understood. We examined gene expression profiles of MPN patients focusing on genes in the JAK-STAT signaling pathway using low-density real-time PCR arrays. We identified the following 2 upregulated genes in MPN patients: a known target of the JAK-STAT axis, SOCS3, and a potentially novel target, SPI1, encoding PU.1. Induction of PU.1 expression by JAK2 V617F in JAK2-wildtype K562 cells and its downregulation by JAK2 siRNA transfection in JAK2 V617F-positive HEL cells supported this possibility. We also found that the ABL1 kinase inhibitor imatinib was very effective in suppressing PU.1 expression in BCR-ABL1-positive K562 cells but not in HEL cells. This suggests that PU.1 expression is regulated by both JAK2 and ABL1. The contribution of the two kinases in driving PU.1 expression was dominant for JAK2 and ABL1 in HEL and K562 cells, respectively. Therefore, PU.1 may be a common transcription factor upregulated in MPN. PU.1 is a transcription factor required for myeloid differentiation and is implicated in erythroid leukemia. Therefore, expression of PU.1 downstream of activated JAK2 may explain why JAK2 mutations are frequently observed in MPN patients.

The JAK2V617F allele burden and STAT3- and STAT5 phosphorylation in myeloproliferative neoplasms: early prefibrotic myelofibrosis compared with essential thrombocythemia, polycythemia vera and myelofibrosis.

Early prefibrotic myelofibrosis (early PMF) is a diagnosis that clinically and histologically mimic essential thrombocythemia (ET), but is important to distinguish from ET, polycythemia vera (PV) and primary myelofibrosis (PMF) due to its different prognosis and clinical evolution. In this study, we assessed the allele burden of JAK2V617F in bone marrow biopsies from patients with these chronic myeloproliferative neoplasms. We correlated our findings with the amount of phosphorylated STAT3 (P-STAT3) and STAT5 (P-STAT5) in megakaryocyte nuclei in the bone marrow. The JAK2V617F allele burden was significantly higher in patients with PV (median: 50.99, range: 23.08-97.29, p < 0.01 and p < 0.01) and PMF (median: 44.13, range: 33.61-92.17, p < 0.05 and p < 0.01) compared with a low allele burden in ET (median: 23.465, range: 8.67-47.92) and early PMF (median: 25.68, range: 0.61-49.13) respectively. In addition, we found a significantly higher phosphorylation of STAT5 and STAT3 in the JAK2V617F positive group than in the negative group. There was no positive correlation between increasing JAK2V617F allele burden and the amount of P-STAT3 and P-STAT5. However, we found low values of P-STAT5 in bone marrow biopsies from patients with ETJAK2V617F+ as compared with patients with early PMFJAK2V617F+. Although this difference was statistically significant, larger studies are needed to firmly support this conclusion.

Uses and abuses of JAK2 and MPL mutation tests in myeloproliferative neoplasms a paper from the 2010 William Beaumont hospital symposium on molecular pathology.

JAK2V617F is sufficiently prevalent in BCR-ABL1-negative myeloproliferative neoplasms (MPNs) to be useful as a clonal marker. JAK2V617F mutation screening is indicated for the evaluation of erythrocytosis, thrombocytosis, splanchnic vein thrombosis, and otherwise unexplained BCR-ABL1-negative granulocytosis. However, the mutation does not provide additional value in the presence of unequivocal morphologic diagnosis, and its presence does not necessarily distinguish one MPN from another or provide useful prognostic information. In general, quantitative cell-based JAK2V617F mutation assays are preferred because the additional information obtained on mutant allele burden enhances diagnostic certainty and facilitates monitoring of response to treatment. JAK2 exon 12 mutation screening is indicated only in the presence of JAK2V617F-negative erythrocytosis that is associated with a subnormal serum erythropoietin level. MPL mutations are neither frequent nor specific enough to warrant their routine use for MPN diagnosis, but they may be useful in resolving specific diagnostic problems. The practice of en bloc screening for JAK2V617F, JAK2 exon 12, and MPL mutations is scientifically irrational and economically irresponsible.

Mouse models of myeloproliferative neoplasms: JAK of all grades.

In 2005, several groups identified a single gain-of-function point mutation in the JAK2 kinase that was present in the majority of patients with myeloproliferative neoplasms (MPNs). Since this discovery, much effort has been dedicated to understanding the molecular consequences of the JAK2V617F mutation in the haematopoietic system. Three waves of mouse models have been produced recently (bone marrow transplantation, transgenic and targeted knock-in), which have facilitated the understanding of the molecular pathogenesis of JAK2V617F-positive MPNs, providing potential platforms for designing and validating novel therapies in humans. This Commentary briefly summarises the first two types of mouse models and then focuses on the more recently generated knock-in models.

New JAK2 inhibitors for myeloproliferative neoplasms.

INTRODUCTION: The discovery of the JAK(V617F) kinase established a common pathogenetic link to the most important types of Philadelphia-chromosome-negative myeloproliferative neoplasms (MPNs): polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). More importantly, the demonstration of constitutive kinase activity emanating from the JAK2 protein provided the rationale for the development of small-molecule JAK2 kinase inhibitors. AREAS COVERED: Several JAK2 kinase inhibitors are being tested in clinical trials for patients with MPNs. In PMF trials, JAK2 inhibitors have been shown to produce rapid reductions in spleen size and marked improvements in constitutional symptoms and quality of life. In ET and/or PV, JAK2 inhibitors normalize hematocrit, platelets and WBC, and spleen size in a large number of patients that are resistant or intolerant to hydroxyurea. JAK2 inhibitors are not specific for the JAK2V617F mutant protein. Rather, they inhibit the JAK2- signal transducer and activator of transcription (STAT) pathway and therefore any patient with MPN may benefit from therapy regardless of JAK2 mutational status. EXPERT OPINION: JAK2 inhibitors induce clinically relevant responses in a large proportion of patients with MPNs. Because JAK kinase activation underlies the pathogenesis of other disorders, such as autoimmune and rheumatological disorders, the paradigm of JAK inhibition may translate into novel therapies for a variety of human diseases.

Correlation of JAK2 V617F mutant allele quantitation with clinical presentation and type of chronic myeloproliferative neoplasm.

Activating JAK2 V617F mutation is present in many patients with chronic myeloproliferative neoplasms. We evaluated, retrospectively, clinical and laboratory data from 70 patients with BCR-ABL1 negative, JAK2 positive, chronic myeloproliferative disease. Quantity of the JAK2 mutant allele was tested for correlation with the clinical presentation, type of chronic myeloproliferative disease, hemoglobin level, white blood cell and platelet counts, spleen size, and/or cardiovascular complications. RealTime-PCR was used for amplification of DNA from marrow or peripheral blood. Polycythemia vera was more frequently diagnosed among patients with >or=50% mutational load than among those with <50% mutational load (71% vs 25%; p = 0.003). Patients with >or=50% mutational load had higher mean white blood cell count (18.6 billion/L vs 11.3 billion/L; p = 0.043). Essential thrombocythemia patients were more likely to have <50% mutational load (48% vs 7%; p = 0.005). Splenomegaly was more frequent in patients with >or=50% mutational load independent of the diagnosis (89% vs 48%; p = 0.03). Cardiovascular complications were reported in 50% of patients with >or=50% mutational load vs 21% of patients with <50% mutational load. JAK2 quantitation was highest in polycythemia vera followed by chronic myeloproliferative disease, unclassifiable, and essential thrombocythemia patients. JAK2 quantitation appears important in clinical evaluation. Mutational load appears to be helpful in stratification of patients into subgroups with different frequency of complications. Quantitation of JAK2 mutational load may be useful in evaluating response to therapy.

Alpha 1,3 fucosyltransferases are master regulators of prostate cancer cell trafficking.

How cancer cells bind to vascular surfaces and extravasate into target organs is an underappreciated, yet essential step in metastasis. We postulate that the metastatic process involves discrete adhesive interactions between circulating cancer cells and microvascular endothelial cells. Sialyl Lewis X (sLe(X)) on prostate cancer (PCa) cells is thought to promote metastasis by mediating PCa cell binding to microvascular endothelial (E)-selectin. Yet, regulation of sLe(X) and related E-selectin ligand expression in PCa cells is a poorly understood factor in PCa metastasis. Here, we describe a glycobiological mechanism regulating E-selectin-mediated adhesion and metastatic potential of PCa cells. We demonstrate that alpha1,3 fucosyltransferases (FT) 3, 6, and 7 are markedly elevated in bone- and liver-metastatic PCa and dictate synthesis of sLe(X) and E-selectin ligands on metastatic PCa cells. Upregulated FT3, FT6, or FT7 expression induced robust PCa PC-3 cell adhesion to bone marrow (BM) endothelium and to inflamed postcapillary venules in an E-selectin-dependent manner. Membrane proteins, CD44, carcinoembryonic antigen (CEA), podocalyxin-like protein (PCLP), and melanoma cell adhesion molecule (MCAM) were major scaffolds presenting E-selectin-binding determinants on FT-upregulated PC-3 cells. Furthermore, elevated FT7 expression promoted PC-3 cell trafficking to and retention in BM through an E-selectin dependent event. These results indicate that alpha1,3 FTs could enhance metastatic efficiency of PCa by triggering an E-selectin-dependent trafficking mechanism.