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1.  Recurrent Somatic TET2 Mutations in Normal Elderly Individuals With Clonal Hematopoiesis 
Nature genetics  2012;44(11):1179-1181.
Aging is characterized by clonal expansion of myeloid-biased hematopoietic stem cells and by an increased risk of myeloid malignancies. Exome sequencing of 3 elderly females with clonal hematopoiesis demonstrated by X-inactivation analysis identified somatic TET2 mutations. Recurrence testing found TET2 mutations in 10 out of 182 individuals with X-inactivation skewing. TET2 mutations were specific to individuals with clonal hematopoiesis without hematologic malignancies and were associated with alterations in DNA methylation.
doi:10.1038/ng.2413
PMCID: PMC3483435  PMID: 23001125
TET2; X-inactivation; clonality; skewing; aging; clonal hematopoiesis; methylation; hydroxymethylation; HUMARA
2.  Antiphospholipid antibodies and thrombosis: association with acquired activated protein C resistance in venous thrombosis and with hyperhomocysteinemia in arterial thrombosis 
Thrombosis and haemostasis  2004;92(6):1312-1319.
Summary
Although antiphospholipid antibodies (aPL) are associated with thrombosis, it is not known who with aPL is at higher risk for thrombosis. It was the aim of this cross-sectional study to investigate how thrombophilic factors contribute to venous or arterial thrombosis in aPL-positive individuals. In outpatient test centres at two tertiary care hospitals, two hundred and eight (208) persons requiring aPL testing were matched by age, gender and centre to 208 persons requiring a complete blood count. Persons were classified as aPL-positive (having anticardiolipin, lupus anticoagulant and/or anti-β2-glycoprotein I antibodies) or aPL-negative. Several thrombophilic factors were studied using logistic regression modelling. Results showed that the aPL-positive group had three-fold more events (37%) than the aPL-negative group (12%). In unadjusted analyses, clinically important associations were observed between factor V Leiden and venous thrombosis, hyperhomocysteinemia and arterial thrombosis, and activated protein C resistance (APCR) and venous thrombosis (OR, 95% CI = 4.00, 1.35–11.91; 4.79, 2.03–11.33; and 2.03, 1.03–3.97, respectively). After adjusting for recruitment group, persons with both APCR and aPL had a three-fold greater risk (OR, 95% CI = 3.31, 1.30–8.41) for venous thrombosis than those with neither APCR nor aPL. Similarly, after adjusting for hypertension, family history of cardiovascular disease, gender and recruitment group, persons with both hyperhomocysteinemia and aPL had a five-fold increased risk (OR, 95% CI = 4.90, 1.37–17.37) for arterial thrombosis compared to those with neither risk factor. In conclusion, APCR phenotype and hyperhomocysteinemia are associated with a higher risk of venous and arterial thrombosis, respectively, in the presence of aPL.
doi:10.1267/THRO04061312
PMCID: PMC3482245  PMID: 15583739 CAMSID: cams2359
Antiphospholipid antibodies; antiphospholipid syndrome; thrombosis; activated protein C resistance; hyperhomocysteinemia
3.  Emerging therapeutic options for myelofibrosis: a Canadian perspective 
Myelofibrosis (MF) is a clonal stem cell disorder characterized by cytopenias, splenomegaly, marrow fibrosis, and systemic symptoms due to elevated inflammatory cytokines. MF is associated with decreased survival. The quality of life of patients with MF is similar to other advanced malignancies. Allogeneic hematopoietic cell transplantation is a curative treatment, but is applicable to a minority of patients with MF. None of the conventional therapies are known to alter the natural history of the disease. Significant progress has been made in the last few years in the understanding of disease biology of MF. Discovery of the JAK2V617F mutation paved the way for drug discovery in MF, and the first JAK1/2 inhibitor, ruxolitinib, has been approved by FDA and Health Canada. Several other JAK1/2 inhibitors are at various stages of clinical development. As a consequence, the therapeutic landscape of MF is changing from a disease where no effective therapies existed to one with several novel treatment options on the horizon. In this report, we assess the changing therapeutic options for MF, and critically analyze the position of novel treatments in the current armamentarium.
PMCID: PMC3484412  PMID: 23119228
Myelofibrosis; JAK1/2; ruxolitinib; splenomegaly; treatment options
4.  The Presence of Multiple Prothrombotic Risk Factors Is Associated with a Higher Risk of Thrombosis in Individuals with Anticardiolipin Antibodies 
The Journal of rheumatology  2003;30(11):2385-2391.
Objective
To explore the effect of multiple prothrombotic risk factors in individuals with anticardiolipin antibodies (aCL), we evaluated immunologic, coagulation, and genetic prothrombotic abnormalities in a cohort of individuals with different aCL titers.
Methods
We recruited 87 individuals into 4 categories (normal, low, intermediate, or high) based on their baseline IgG aCL (aCL-IgG) titers. We measured at followup: repeat aCL-IgG, IgM aCL (aCL-IgM), antibodies to β2-glycoprotein I (anti-β2-GPI), lupus anticoagulant (LAC) antibodies, protein C, protein S, activated protein C resistance, factor V506 Leiden mutation, methyl tetrahydrofolate reductase (MTHFR) C677T genotype, and prothrombin 20210A gene mutation. Thrombotic events were confirmed.
Results
At recruitment, 20 individuals were negative for aCL-IgG and 67 were positive (22 low, 20 intermediate, and 25 high titer). Twenty of the 87 participants had experienced a previous thrombotic event: 4 in the aCL-IgG negative group and 16 in the aCL-IgG positive group. Among the 87 individuals, the number of those with concomitant prothrombotic risk factors was as follows: 5 had no other prothrombotic risk factors, 32 had 1 risk factor, 24 had 2 risk factors, 10 had 3 risk factors, 10 had 4 risk factors, and 6 had 5 risk factors. Thrombotic events were observed in 20%, 13%, 33%, 10%, 30%, and 50% of these groups, respectively, and the odds ratio associated with a previous thrombotic event was 1.46 per each additional prothrombotic risk factor (95% confidence interval: 1.003–2.134).
Conclusion
In individuals with positive aCL-IgG, we observed an association between the number of prothrombotic risk factors and history of thrombotic events. (J Rheumatol 2003;30:2385–91)
PMCID: PMC3440310  PMID: 14677182 CAMSID: cams2358
THROMBOSIS; ANTIBODIES; ANTICARDIOLIPIN; LUPUS COAGULATION INHIBITOR; THROMBOPHILIA; FACTOR V
5.  No evidence that skewing of X chromosome inactivation patterns is transmitted to offspring in humans 
Skewing of X chromosome inactivation (XCI) can occur in normal females and increases in tissues with age. The mechanisms underlying skewing in normal females, however, remain controversial. To better understand the phenomenon of XCI in nondisease states, we evaluated XCI patterns in epithelial and hematopoietic cells of over 500 healthy female mother-neonate pairs. The incidence of skewing observed in mothers was twice that observed in neonates, and in both cohorts, the incidence of XCI was lower in epithelial cells than hematopoietic cells. These results suggest that XCI incidence varies by tissue type and that age-dependent mechanisms can influence skewing in both epithelial and hematopoietic cells. In both cohorts, a correlation was identified in the direction of skewing in epithelial and hematopoietic cells, suggesting common underlying skewing mechanisms across tissues. However, there was no correlation between the XCI patterns of mothers and their respective neonates, and skewed mothers gave birth to skewed neonates at the same frequency as nonskewed mothers. Taken together, our data suggest that in humans, the XCI pattern observed at birth does not reflect a single heritable genetic locus, but rather corresponds to a complex trait determined, at least in part, by selection biases occurring after XCI.
doi:10.1172/JCI33166
PMCID: PMC2147671  PMID: 18097474
6.  Prediction of Graft-Versus-Host Disease in Humans by Donor Gene-Expression Profiling 
PLoS Medicine  2007;4(1):e23.
Background
Graft-versus-host disease (GVHD) results from recognition of host antigens by donor T cells following allogeneic hematopoietic cell transplantation (AHCT). Notably, histoincompatibility between donor and recipient is necessary but not sufficient to elicit GVHD. Therefore, we tested the hypothesis that some donors may be “stronger alloresponders” than others, and consequently more likely to elicit GVHD.
Methods and Findings
To this end, we measured the gene-expression profiles of CD4+ and CD8+ T cells from 50 AHCT donors with microarrays. We report that pre-AHCT gene-expression profiling segregates donors whose recipient suffered from GVHD or not. Using quantitative PCR, established statistical tests, and analysis of multiple independent training-test datasets, we found that for chronic GVHD the “dangerous donor” trait (occurrence of GVHD in the recipient) is under polygenic control and is shaped by the activity of genes that regulate transforming growth factor-β signaling and cell proliferation.
Conclusions
These findings strongly suggest that the donor gene-expression profile has a dominant influence on the occurrence of GVHD in the recipient. The ability to discriminate strong and weak alloresponders using gene-expression profiling could pave the way to personalized transplantation medicine.
The donor gene expression profile appears to have a dominant influence on the occurrence of graft-versus-host disease in the recipient.
Editors' Summary
Background.
Human blood contains red blood cells, white blood cells, and platelets, which carry oxygen throughout the body, fight infections, and help blood clot, respectively. Normally, blood-forming (hematopoietic) stem cells in the bone marrow (and their offspring, peripheral blood stem cells) continually provide new blood cells. Tumors that arise from the bone marrow (such as leukemia and lymphoma, two types of hematopoietic tumor) are often treated by a bone marrow or peripheral blood stem cell transplant from a healthy donor to provide new blood-forming stem cells, as a follow-up to chemotherapy or radiotherapy designed to eradicate as much of the tumor as possible. This procedure is called allogeneic hematopoietic cell transplantation (AHCT)—the word allogeneic indicates that the donor and recipient are not genetically identical. When solid organs (for example, kidneys) are transplanted, the recipient's immune system can recognize alloantigens (proteins that vary between individuals) on the donor organ as foreign and reject it. To reduce the risk of rejection, the donor and recipient must have identical major histocompatibility complex (MHC) proteins. MHC matching is also important in AHCT but for further reasons. Here, donor T lymphocytes (a type of white blood cell) can attack the skin and other tissues of the host. This graft versus host disease (GVHD) affects many people undergoing AHCT despite MHC matching either soon after transplantation (acute GVHD) or months later (chronic GVHD). As an aside, the transplant may also act against the tumor itself—this is known as a graft versus leukemia effect.
Why Was This Study Done?
GVHD can usually be treated with drugs that damp down the immune system (immunosuppressive drugs), but it would be preferable to avoid GVHD altogether. Indeed, GVHD continues to be the leading cause of nonrelapse mortality following AHCT. Unfortunately, what determines who will develop GVHD after MHC-matched AHCT is unclear. Although GVHD only develops if there are some mismatches in histocompatibility antigens between the donor and host, it does not inevitably develop. Until now, scientists have mainly investigated whether differences between ACHT recipients might explain this observation. But, in this study, the researchers have examined the donors instead to see whether differences in their immune responses might make some donors stronger “alloresponders” than others and consequently more likely to cause GVHD.
What Did the Researchers Do and Find?
The researchers used a molecular biology technique called microarray expression profiling to examine gene expression patterns in the T lymphocytes of peripheral blood stem cell donors. From these patterns, they identified numerous genes whose expression levels discriminated between donors whose MHC-identical transplant recipient developed GVHD after AHCT (GVHD+ donors) and those whose recipient did not develop GVHD (GVHD− donors). The researchers confirmed that the expression levels of 17 of these genes discriminated between GVHD+ and GVHD− donors using a second technique called quantitative reverse transcriptase polymerase chain reaction. Many of these genes are involved in TGF-β signaling (TGF-β is a protein that helps to control the immune system), cell growth, or proliferation. The researchers also identified four gene pairs that interacted with each other to determine the likelihood that a given donor would induce GVHD. Finally, the researchers computationally retested their data and showed that the measurement of expression levels of each of these genes and of the four interacting gene pairs could correctly identify a donor sample likely to cause GVHD in up to 80% of samples.
What Do These Findings Mean?
These findings provide the first evidence that the donor's gene expression profile influences the development of GVHD in the recipient after AHCT. The researchers suggest that a “dangerous donor” (strong alloresponder) is a key factor in determining whether GVHD occurs after AHCT and propose that gene expression profiling of donor T lymphocytes might identify those donors likely to cause GVHD. Before this approach can be used to reduce the incidence of GVHD after AHCT, these findings need to be confirmed in many more donors. Also, the development of a test that is accurate enough for clinical use—one that does not miss dangerous donors but does not discard too many safe donors—may require the identification of larger groups of interacting genes. But, if it survives further investigation, the concept of a dangerous donor could represent an important advance in transplantation medicine, one that could help clinicians select low-risk donors for AHCT and tailor patients' immunosuppressive drug regimens according to their donor-determined risk of GVHD.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/doi:10.1371/journal.pmed.0040023.
• The National Marrow Donor Program provides information for patients and physicians on all aspects of hematopoietic stem cell transplantation, including GVHD
• The MedlinePlus encyclopedia has pages on bone marrow transplants, GVHD and transplant rejection
• The US National Cancer Institute has a factsheet on bone marrow and peripheral blood stem cell transplantation
doi:10.1371/journal.pmed.0040023
PMCID: PMC1796639  PMID: 17378698

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