Predictive values of X-chromosome inactivation patterns and clinicohematologic parameters for vascular complications in female patients with essential thrombocythemia

Essential thrombocythemia (ET) is a heterogeneous disorder in which the clonality of hematopoiesis varies. The clinical significance of clonality status in ET remains to be determined. We used the human androgen receptor gene (HUMARA)–polymerase chain reaction assay to investigate X-chromosome inactivation patterns (XCIPs) and their value in predicting vascular complications in 89 female patients with ET. Fifty-four (68.4%) patients had a clonal pattern of XCIP, and 15 (19.0%) had a polyclonal pattern. The remaining 20 patients had either an ambiguous or a homozygous pattern of XCIP and were therefore excluded from further analysis. Patients with clonal XCIPs were older (P = .029) and were at greater risk for thrombosis (P = .007) than were those with polyclonal XCIPs. We did not find a correlation between the occurrence of hemorrhage and XCIP (P = .492). Advanced age was predictive of thrombosis and hemorrhage. Platelet count did not influence the risk for vascular complications. Hypertension was significantly correlated with thrombotic events (P = .002), whereas diabetes mellitus and hypercholesterolemia were of no predictive value. In a multivariate analysis, age was the significant predictor of thrombosis (P = .030); however, XCIPs (P = .083) and hypertension (P = .073) tended to predict thrombosis. Our results suggest that older patients who have clonal XCIPs or hypertension are at increased risk for thrombosis and should be monitored closely for this complication.

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EEC Growth, JAK2 Mutation, PRV-1 Overexpression and X-Chromosome Inactivation Pattern: Predicting Values on Polycythemia Vera Evolution and Risk of Thrombosis in Idiopathic Thrombocytosis.

Blood ◽

10.1182/blood.v108.11.2692.2692 ◽

2006 ◽

Vol 108 (11) ◽

pp. 2692-2692

Author(s):

Lee-Yung Shih ◽

Ching-Tai Lee ◽

Tung-Liang Lin ◽

Chia-Hui Chang ◽

Chein-Fuang Huang ◽

...

Keyword(s):

X Chromosome ◽

Bone Marrow Cells ◽

Vascular Complications ◽

X Chromosome Inactivation ◽

Initial Presentation ◽

Chromosome Inactivation ◽

Pcr Assay ◽

Jak2 Mutation ◽

Female Patients ◽

Inactivation Pattern

Abstract We have previously demonstrated that endogenous erythroid colony (EEC) growth could predict PV evolution in idiopathic thrombocytosis (IT) (Blood 83:744, 1994). We also showed that female patients with IT and monoclonal X-chromosome inactivation pattern (XCIP) had a high risk of vascular complications (Blood100:1596, 2002). Recently, PRV-1 overexpression and JAK2V617F mutation have been described and implicated in the diagnosis of Ph(-) chronic myeloproliferative disorders. In a large cohort of patients with IT, we aimed to determine the correlation among the molecular markers of EEC growth, JAK2 mutation status, PRV-1 level and XCIP, and to assess the predicting values of these biomarkers on PV evolution and risk of thrombosis. Allele-specific PCR assay was used to detect JAK2V617F in peripheral blood granulocytes (n=178) or bone marrow cells (n=75) from patients with IT. EEC assay was performed on 235 patients in a serum-free culture system at initial diagnosis. PRV-1 mRNA expression in granulocytes from 187 patients was measured by real-time RQ-PCR assay and expressed as the copy number of PRV-1 normalized to GAPDH gene (NCN). Clonality analysis of XCIP with HUMARA-PCR assay was performed on 123 female patients. JAK2V617F was detected in 57.7% of patients with IT. Forty-one percent of IT patients had EEC growth at initial presentation. Of those analyzed for PRV-1 levels, 138 patients had not received platelet-lowering agents at time of analysis; 72 (38.5%) had PRV-1 overexpression with NCN ≥ 1 (NCN of 30 normal subjects, mean±SE: 0.32±0.04, range: 0.04–0.97). Seventy-six female patients had monoclonal XCIP and 28 had polyclonal XCIP; the remaining 19 patients had ambiguous or homozygous pattern of XCIP. EEC growth was strongly correlated with JAK2 mutation (P<0.0001) and PRV-1 overexpression (P<0.0001). PRV-1 overexpression was highly associated with JAK2 mutation (P<0.0001) and monoclonal XCIP (P=0.003). The frequency of JAK2 mutation or EEC growth was not different between monoclonal and polyclonal XCIP. Thirty-four patients subsequently developed PV (IT-PV), ranging from 1.5 months to 90 months. All 34 IT-PV patients had EEC growth and all but one harbored JAK2 mutation at initial presentation. Patients with IT-PV had a significantly higher frequency of EEC(+) (P<0.0001), JAK2(+) (P<0.0001), and PRV-1(+) (P<0.0001) than those without PV evolution, whereas there was no difference in age (P=0.914) or XCIP (P=0.550) between IT with and without PV evolution. One hundred and sixty-nine patients had all biomarkers of JAK2/EEC/PRV-1 analyzed, 57 patients were JAK2(+)/EEC(+)/PRV-1(+) and 55 were JAK2(-)/EEC(-)/PRV-1(-). Eighteen patients with all 3 biomarkers-positive developed PV later compared with none of patients with all 3 biomarkers-negative (P<0.0001). Eighty-two patients experienced thrombotic complications during their disease courses. The occurrence of thrombosis was strongly associated with EEC growth (P=0.0002), JAK2 mutation (P=0.007), PRV-1 level (P=0.004), and XCIP (P=0.034). The present study showed that EEC growth and JAK2 mutation were predictors of PV evolution; EEC growth, JAK2 mutation, PRV-1 overexpression and monoclonal XCIP predicted the risk of thrombosis in patients with IT.

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High frequency of the X-chromosome inactivation in young female patients with high-grade glioma

Diagnostic Pathology ◽

10.1186/1746-1596-8-101 ◽

2013 ◽

Vol 8 (1) ◽

Cited By ~ 3

Author(s):

Gang Li ◽

Zhiguo Zhang ◽

Tianbo Jin ◽

Hongjuan Liang ◽

Yanyang Tu ◽

...

Keyword(s):

X Chromosome ◽

High Frequency ◽

High Grade Glioma ◽

Young Female ◽

X Chromosome Inactivation ◽

Chromosome Inactivation ◽

High Grade ◽

Female Patients

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Long-term serial analysis of X-chromosome inactivation patterns and JAK2 V617F mutant levels in patients with essential thrombocythemia show that minor mutant-positive clones can remain stable for many years

Blood ◽

10.1182/blood-2006-06-029769 ◽

2006 ◽

Vol 109 (3) ◽

pp. 1241-1243 ◽

Cited By ~ 43

Author(s):

Rosemary E. Gale ◽

Anthony J.R. Allen ◽

Michael J. Nash ◽

David C. Linch

Keyword(s):

X Chromosome ◽

Essential Thrombocythemia ◽

Jak2 V617f ◽

X Chromosome Inactivation ◽

Janus Kinase ◽

Chromosome Inactivation ◽

Jak2 Mutation ◽

Clone Size ◽

Cell Patterns

Abstract Essential thrombocythemia (ET) is heterogeneous with respect to natural history, X-chromosome inactivation patterns (XCIPs), and presence of the V617F mutation in Janus kinase 2 (JAK2). We studied 111 patients with ET; 39% were JAK2 mutant positive, and clone size (percentage mutant JAK2) was concordant with XCIP when constitutive T-cell patterns were taken into account. JAK2 mutant clones were present in both clonal and polyclonal cases as determined by XCIP, and the former had higher mutant JAK2 levels (median 26% versus 16%; P = .001). No change was observed in serial XCIP analysis of 14 polyclonal patients over a median follow-up of 61 months. Furthermore, 18 of 19 mutant-positive patients showed no significant change in mutant JAK2 level over a median follow-up of 47 months. These results suggest that, in many cases of ET, a small stable clone containing a JAK2 mutation can be maintained as a subpopulation for many years.

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Clonality Analysis of Hematopoiesis in Essential Thrombocythemia: Advantages of Studying T Lymphocytes and Platelets

Blood ◽

10.1182/blood.v89.1.128 ◽

1997 ◽

Vol 89 (1) ◽

pp. 128-134 ◽

Cited By ~ 124

Author(s):

Nahed El-Kassar ◽

Gilles Hetet ◽

Jean Brière ◽

Bernard Grandchamp

Keyword(s):

T Lymphocytes ◽

X Chromosome ◽

Essential Thrombocythemia ◽

Hematopoietic Cells ◽

X Chromosome Inactivation ◽

Chromosome Inactivation ◽

Pcr Analysis ◽

Clonal Hematopoiesis ◽

Control Tissue ◽

Clonality Analysis

Abstract Essential thrombocythemia (ET) is a myeloproliferative disorder characterized by a sustained elevation of the platelet count in the absence of other causes of thrombocytosis. ET is difficult to diagnose, and the demonstration of clonal hematopoiesis may be of value. However, clonality analysis of hematopoietic cells based on the study of the X-chromosome inactivation pattern is complicated by the observation that some normal females present skewed lyonization. Moreover, DNA methylation of X-linked genes in hematopoietic cells may differ from that in other tissues. Appropriate controls for skewed lyonization are therefore critical for the study of clonality. We developed two techniques based on X-chromosome inactivation and polymerase chain reaction (PCR) analysis of polymorphisms, to study clonality in ET patients. Reverse transcriptase-PCR analysis of IDS, P55, and G6PD mRNAs was used to examine the different hematopoietic cell lineages including platelets in patients heterozygous for these polymorphisms and analysis of the HUMARA gene methylation pattern permitted us to study clonality in all nucleated cell fractions of the other patients. Using both types of assay and T lymphocytes as a control tissue for lyonization, clonal hematopoiesis was demonstrated in 28 patients. In 14 patients, the granulocytes were polyclonal; among these patients, platelets were monoclonal in 3 cases, polyclonal in 7 cases, and in the remaining 4 cases this fraction could not be studied because the patients were homozygotes for all RNA markers. No conclusion about clonality could be drawn in 6 cases. Polyclonal hematopoiesis was found in all the cases of reactive thrombocytosis. These findings confirm the high frequency of monoclonal hematopoiesis in ET, the utility of studying platelets, and the possibility of using T lymphocytes as a control tissue for X-chromosome inactivation patterns.

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X chromosome inactivation pattern in female patients with breast cancer

Breast Cancer Research ◽

10.1186/bcr148 ◽

2000 ◽

Vol 2 (S1) ◽

Cited By ~ 1

Author(s):

M Kristiansen ◽

A Langer ◽

GP Knudsen ◽

BL Weber ◽

A-L Børresen-Dale ◽

...

Keyword(s):

Breast Cancer ◽

X Chromosome ◽

X Chromosome Inactivation ◽

Chromosome Inactivation ◽

Female Patients ◽

Inactivation Pattern

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Clonal patterns of X-chromosome inactivation in female patients withaplastic anaemia studied using a novel reverse transcription polymerase chain reaction method

European Journal Of Haematology ◽

10.1034/j.1600-0609.2000.90150.x ◽

2000 ◽

Vol 64 (6) ◽

pp. 385-395 ◽

Cited By ~ 8

Author(s):

Y. Mortazavi ◽

R. Chopra ◽

E. C. Gordon-Smith ◽

T. R. Rutherford

Keyword(s):

Polymerase Chain Reaction ◽

X Chromosome ◽

Reverse Transcription ◽

Polymerase Chain Reaction Method ◽

X Chromosome Inactivation ◽

Chromosome Inactivation ◽

Chain Reaction ◽

Reaction Method ◽

Female Patients ◽

Polymerase Chain

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X-chromosome inactivation in female patients with Fabry disease

Clinical Genetics ◽

10.1111/cge.12613 ◽

2015 ◽

Vol 89 (1) ◽

pp. 44-54 ◽

Cited By ~ 132

Author(s):

L. Echevarria ◽

K. Benistan ◽

A. Toussaint ◽

O. Dubourg ◽

A.A. Hagege ◽

...

Keyword(s):

Fabry Disease ◽

X Chromosome ◽

X Chromosome Inactivation ◽

Chromosome Inactivation ◽

Female Patients

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X Chromosome Inactivation Pattern is not Associated With Interindividual Variations in Thyroid Volume: A Study of Euthyroid Danish Female Twins

Twin Research and Human Genetics ◽

10.1375/twin.12.5.502 ◽

2009 ◽

Vol 12 (5) ◽

pp. 502-506 ◽

Cited By ~ 2

Author(s):

Thomas Heiberg Brix ◽

Pia Skov Hansen ◽

Finn Noe Bennedbæk ◽

Steen Joop Bonnema ◽

Kirsten Ohm Kyvik ◽

...

Keyword(s):

X Chromosome ◽

Twin Pair ◽

Receptor Gene ◽

Thyroid Volume ◽

X Chromosome Inactivation ◽

Cag Repeat ◽

Chromosome Inactivation ◽

Pcr Analysis ◽

Autoimmune Thyroid ◽

The Impact

AbstractAhigher frequency of skewed X chromosome inactivation (XCI) is found in patients with autoimmune thyroid disease (AITD) than in controls. Although goitre is often present in AITD, a recent study failed to show an association between XCI and clinically overt nontoxic goitre. However, the etiology of overt goitre is complex, and the mechanisms influencing thyroid volume may involve fewer factors than the mechanisms underlying overt goitre. In order to examine the impact of XCI on thyroid volume in euthyroid females, we studied whether within cohort (n= 138) and within twin pair (n= 69) differences in XCI are correlated with differences in thyroid volume. XCI was determined by PCR analysis of a polymorphic CAG repeat in the first exon of the androgen receptor gene. Thyroid volume was determined by ultrasound. Neither in the within cohort nor in the within twin pair analysis could we demonstrate a statistically significant association between XCI and thyroid volume: Regression coefficient (β) = 0.023 (95% confidence interval, –0.062–0.108),p= 0.592 and β = 0.038 (–0.080–0.156),p= 0.521, respectively. Controlling for potential confounders such as zygosity, age, TSH, smoking habits and use of oral contraceptives did not change the findings. In conclusion, in a sample of euthyroid Danish female twins, we found no evidence of a relationship between XCI pattern and thyroid volume.

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