Leukemia & Lymphoma, 2015; Early Online: 1–3 © 2015 Informa UK, Ltd. ISSN: 1042-8194 print / 1029-2403 online DOI: 10.3109/10428194.2015.1046065
LETTER TO THE EDITOR
The glucocorticoid receptor A3669G SNP is not associated with polycythemia vera, essential thrombocythemia or primary myelofibrosis Roxana M. Costache1, Claudia Bănescu2, Radu A. Popp1, Ioan V. Pop1 & Adrian P. Trifa1 1Department of Medical Genetics, “Iuliu Hatieganu” University of Medicine and Pharmacy, Cluj-Napoca, Romania, and
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2Department of Genetics, University of Medicine and Pharmacy, Tîrgu-Mureș, Romania
The myeloproliferative neoplasms (MPNs) are a group of hematological malignancies characterized by clonal proliferation of one or several myeloid cell lines. There are three classic types of MPN, negative for BCR-ABL fusion: polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF). More than 90% of the PV patients and around 50% of the ET and PMF patients harbor the JAK2 V617F mutation. The MPL exon 12 mutations and CALR exon 9 indels were further demonstrated in around 5% and 30%, respectively, of the ET and PMF patients. The somatic mutations seen in patients with PV, ET and PMF lead to constitutive activation of the JAK-STAT signaling pathway, even in the absence of hematopoietic growth factors, such as erythopoietin and thrombopoietin [1]. The hematopoiesis requires a complex interplay between various growth factors, receptors and transcription factors. Among these factors, the glucocorticoid receptor (GR) interferes with the myeloid hematopoiesis process in at least two points. The first one consists of GATA-1 binding, and the second one marked by the cooperation with the activated erythropoietin receptor and stem cell factor receptor. The role of the GR emerged from interesting observations. Patients having a constitutive activation of the GR (usually under an excess of gluco-corticoids) usually develop erythrocytosis. On the other hand, patients with del(5q) syndrome (a form of myelodysplastic syndrome), who are GR haploinsufficient (the GR gene is situated at 5q31-32), often present with erythropoietin-resistant anemia [2,3]. The GR gene is polymorphic. Among its polymorphisms, the A3669G singlenucleotide polymorphism (SNP) in exon 9 of GR stabilizes the mRNA and increases the expression of GRβ. The unique structure of GRβ impairs the ligand-binding domain, induces nuclear retention and the inability to form complexes with other signaling partners such as the phosphorylated form of STAT-5. Furthermore, this isoform creates heterodimers and acts as a dominant negative regulator of GR function that
leads to a poor response to corticosteroids [4,5]. Considering the important role that the GR plays in hematopoiesis, Varricchio et al. and Poletto et al. searched for correlations between the A3669G SNP and MPNs. They found indeed a positive association between this SNP, and PV and PMF, respectively [4,6]. We aimed to explore this hypothesis on a large cohort of Romanian patients with MPNs – PV, ET and PMF. The study was based on a case-control design with two groups. The first one consists of 388 MPNs patients divided as follows: 170 with ET, 161 with PV and 57 with PMF. A total of 138 patients with PV (86%), 94 patients with ET (55%), and 25 patients with PMF (44%) were positive for JAK2 V617F mutation. The CALR indels characterized 35 patients with ET (21%) and 17 patients with PMF (30%). MPL mutations were rare events, seen in three patients with ET (1.8%) and two patients with PMF (3.5%). The diagnosis of all the MPN patients was reviewed according to the 2008 WHO classification of the myeloid neoplasms [7]. The control group consisted in 448 individuals age- and sex-matched to the patients. The controls were free of any malignancies, including the hematological ones. The GR polymorphism was investigated using a PCR-RFLP protocol, as previously described [5,8]. The distribution of qualitative variables was compared by the Fisher ’s exact test, while the Mann-Whitney test was used to compare the medians of the quantitative variables. The study was approved by the Ethics Committee of the “Iuliu Hatieganu” University of Medicine and Pharmacy, ClujNapoca, Romania. Written consent was obtained from all the participants to the study. The G/A genotype was detected in 65 patients with PV (OR ⫽ 0.9; 95 % CI ⫽ 0.6–1.4; p ⫽ 0.8), 64 patients with ET (OR ⫽ 1; 95 % CI ⫽ 0.7–1.5; p ⫽ 0.7), and 23 patients with PMF (OR ⫽ 0.9; 95% CI ⫽ 0.5–1.5; p ⫽ 0.7), compared to 174 individuals in the control group.
Correspondence: Adrian P. Trifa, MD, PhD, Department of Medical Genetics, “Iuliu Hat ieganu” University of Medicine and Pharmacy, 6, Pasteur Street, ´ 400349, Cluj-Napoca, Romania. Tel: ⫹ 40 750 774406. Fax: ⫹ 40 264 598606. E-mail: [email protected] Received 3 March 2015; accepted 17 April 2015
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R. M. Costache et al.
Table I. Genotypes and allele frequencies for the A3669G SNP. PV group ET group PMF group MPN (all) Controls
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A3669G SNP Genotype; n (%) A/A 92 (57) G/A 65 (40) G/G 4 (3) 69 (43) G/A ⫹ G/G Total 161 (100) Allele frequency; n (%) A 249 (77) G 73 (23) Total 322 (100)
101 (59) 64 (38) 5 (3) 69 (41)
30 (53) 23 (40) 4 (7) 27 (47)
223 (57) 152 (39) 13 (4) 165 (43)
255 (57) 174 (39) 19 (4) 193 (43)
170 (100) 57 (100)
388 (100)
448 (100)
266 (78) 83 (73) 74 (22) 31 (27) 340 (100) 114 (100)
598 (77) 178 (23) 776 (100)
684 (76) 212 (24) 896 (100)
The G/G genotype was observed in four patients with PV (OR ⫽ 1.7; 95 % CI ⫽ 0.5–5.1; p ⫽ 0.4), five patients with ET (OR ⫽ 1.5; 95% CI ⫽ 0.5–4.1; p ⫽ 0.4), and four patients with PMF (OR ⫽ 0.5; 95% CI ⫽ 0.17–1.7; p ⫽ 0.3), compared to 19 individuals from the control group. We also analyzed the combined variant genotypes (G/A ⫹ G/G), again without reaching statistical significance (p ⫽ 1 for PV, 0.58 for ET, 0.5 for PMF and 0.88 for the whole MPN cohort). Thus, the G allele had a similar frequency in patients with MPN and controls (p ⫽ 0.75 for PV, 0.49 for ET, 0.41 for PMF, and 0.7 for the whole MPN cohort). To determine whether the G allele favored the acquisition of JAK2 V617F mutation, we analyzed the frequency of GR SNP genotypes and of G allele in patients stratified after the JAK2 V617F genotype. The A3669G SNP was not enriched in JAK2 V617F-positive versus JAK2 V617F-negative patients (OR ⫽ 1.1; 95% CI ⫽ 0.72–1.7; p ⫽ 0.6). Also when comparing the JAK2 V617F-positive patients and controls, we observed a similar distribution of the A3669G SNP. The G allele was also similarly distributed between JAK2 V617F-positive and JAK2 V617F-negative patients (p ⬎ 0.5). Regarding the CALR mutation status in patients with ET and PMF, the G/A and G/G genotypes of the A3669G were similarly distributed in patients with and without CALR indels (OR ⫽ 1; 95% CI ⫽ 0.5–1.8; p ⫽ 1), and also in patients with CALR indels patients versus controls (OR ⫽ 1; 95% CI ⫽ 0.6–1.8; p ⫽ 0.8). We also attempted to establish the relationship between the A3669G SNP and laboratory (hemoglobin, white blood cells and the platelets at diagnosis) and clinical (thrombosis and splenomegaly) parameters. None of these parameters was associated with the A3669G SNP (p ⬎ 0.05 for all comparisons in all three diseases). Genotypes and allele frequencies of the GR A3669G SNP in our population of patients with MPNs and the control group are listed in detail in Table I. Among all the correlations that were performed, none reached statistical significance. Our findings showed that A3669G SNP of the GR is not implicated in the occurrence of PV, ET or PMF, regardless of the mutation status (e.g. JAK2 V617F or CALR). Varrichio et al. analyzed the GR A3669G SNP in 57 MPN patients (22 PV, 15 ET and 20 PMF) and 22 controls. Real time PCR was used to measure the JAK2 V617F mutation, while GR SNP was determined with single-strand conformation polymorphism (SSCP). They also performed mRNA isolation, Western blot and immune precipitation analyses on the erythroblasts expansion
cultures of mononuclear cells from 19 healthy donors and 16 patients with PV. Their results show that A3669G polymorphism had greater frequency in PV (55%, p ⫽ 0.0028) and PMF (35%) patients than in controls (9%) or patients with ET (6%). Regarding the PV cell culture, they obtained a great number of immature erythroblasts with low levels of GR β-globin indifferent for dexamethasone stimulation. Further, the levels of GRβ expressed by erythroblasts from four PV patients and four controls were compared by quantitative RT-PCR and the outcomes were increased 3 times for PV patients (p ⬍ 0.001) [4]. A study of 58 Diamond-Blackfan anemia patients led also by Varrichio et al., demonstrated a correlation between this GR SNP and this rare congenital form of red cell aplasia [5]. Poletto et al. investigated the frequency of GR polymorphism and its impact on disease phenotype and progression in 499 patients with PMF. They also took into account other factors such as white blood cell count, percentage of blasts, and IPSS prognostic score. The results show that the G allele occurred significantly more frequently in PMF patients (26.2%) compared with 111 healthy volunteers (18.2%; OR, 1.62; 95% CI, 1.12–2.34; p ⫽ 0.009). The G/G genotype was associated with higher WBC count, splenomegaly, higher frequency of circulating CD34 ⫹ cells at diagnosis and also with shorter overall survival (77.6 vs. 298 months, p ⫽ 0.049) and blast transformation-free survival (76.7 vs. 261 months; p ⫽ 0.018). The correlation remained significant after correction for the JAK2 V617F genotype [6]. Interestingly, positive associations between the same GR SNP and several diseases, such as: lupus erythematosus (27%), rheumatoid arthritis (42%) or central adiposity (30%), were found in the past, suggesting that this SNP has consequences in several various metabolic pathways [3]. In conclusion, we were not able to replicate the positive association between the GR A3669G SNP and MPNs, seen in previous studies. In our large cohort of patients with PV, ET and PMF, this SNP had a similar distribution as in the general population. This was also the case for the molecular subtypes of the MPN (e.g. JAK2 V617F and CALR mutated).
Acknowledgements This study would have not been possible without the help of our colleague and friend Dr Andrei Cucuianu. Unfortunately, he passed away while the study was in progress. The study was supported by Internal Research Grants from the Universities of Medicine and Pharmacy Cluj-Napoca and Tîrgu-Mures to RMC (grant number 1493/2/28.01.2014) and ´ CB (grant number 1/30.01.2013). Potential conflict of interest: Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.
References [1] Cazzola M, Kralovics R. From Janus kinase 2 to calreticulin: the clinically relevant genomic landscape of myeloproliferative neoplasms. Blood 2014;123:3714–3719.
GR A3669G SNP in MPN
Leuk Lymphoma Downloaded from informahealthcare.com by Nyu Medical Center on 06/21/15 For personal use only.
[2] Chang TJ, Scher BM, Waxman S, et al. Inhibition of mouse GATA-1 function by the glucocorticoid receptor: possible mechanism of steroid inhibition of erythroleukemia cell differentiation. Mol Endocrinol 1993;7:528–542. [3] Varricchio L, Migliaccio AR. The role of glucocorticoid receptor (GR) polymorphisms in human erythropoiesis. Am J Blood Res 2014;4:53–72. [4] Varricchio L, Masselli E, Alfani E, et al. The dominant negative β isoform of the glucocorticoid receptor is uniquely expressed in erythroid cells expanded from polycythemia vera patients. Blood 2011;118:425–436. [5] Varricchio L, Godbold J, Scott SA , et al. Increased frequency of the glucocorticoid receptor A3669G (rs6198) polymorphism in patients with Diamond-Blackfan anemia. Blood 2011;118:473–474.
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[6] Poletto V, Rosti V, Villani L, et al. A3669G polymorphism of glucocorticoid receptor is a susceptibility allele for primary myelofibrosis and contributes to phenotypic diversity and blast transformation. Blood 2012;120:3112–3117. [7] Tefferi A , Vardiman JW. Classification and diagnosis of myeloproliferative neoplasms: the 2008 World Health Organization criteria and point-of-care diagnostic algorithms. Leukemia 2008;22: 14–22. [8] Derijk RH, Schaaf MJ, Turner G, et al. A human glucocorticoid receptor gene variant that increases the stability of the glucocorticoid receptor beta-isoform mRNA is associated with rheumatoid arthritis. J Rheumatol 2001;28:2383–2388.
LETTER TO THE EDITOR
The glucocorticoid receptor A3669G SNP is not associated with polycythemia vera, essential thrombocythemia or primary myelofibrosis Roxana M. Costache1, Claudia Bănescu2, Radu A. Popp1, Ioan V. Pop1 & Adrian P. Trifa1 1Department of Medical Genetics, “Iuliu Hatieganu” University of Medicine and Pharmacy, Cluj-Napoca, Romania, and
Leuk Lymphoma Downloaded from informahealthcare.com by Nyu Medical Center on 06/21/15 For personal use only.
2Department of Genetics, University of Medicine and Pharmacy, Tîrgu-Mureș, Romania
The myeloproliferative neoplasms (MPNs) are a group of hematological malignancies characterized by clonal proliferation of one or several myeloid cell lines. There are three classic types of MPN, negative for BCR-ABL fusion: polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF). More than 90% of the PV patients and around 50% of the ET and PMF patients harbor the JAK2 V617F mutation. The MPL exon 12 mutations and CALR exon 9 indels were further demonstrated in around 5% and 30%, respectively, of the ET and PMF patients. The somatic mutations seen in patients with PV, ET and PMF lead to constitutive activation of the JAK-STAT signaling pathway, even in the absence of hematopoietic growth factors, such as erythopoietin and thrombopoietin [1]. The hematopoiesis requires a complex interplay between various growth factors, receptors and transcription factors. Among these factors, the glucocorticoid receptor (GR) interferes with the myeloid hematopoiesis process in at least two points. The first one consists of GATA-1 binding, and the second one marked by the cooperation with the activated erythropoietin receptor and stem cell factor receptor. The role of the GR emerged from interesting observations. Patients having a constitutive activation of the GR (usually under an excess of gluco-corticoids) usually develop erythrocytosis. On the other hand, patients with del(5q) syndrome (a form of myelodysplastic syndrome), who are GR haploinsufficient (the GR gene is situated at 5q31-32), often present with erythropoietin-resistant anemia [2,3]. The GR gene is polymorphic. Among its polymorphisms, the A3669G singlenucleotide polymorphism (SNP) in exon 9 of GR stabilizes the mRNA and increases the expression of GRβ. The unique structure of GRβ impairs the ligand-binding domain, induces nuclear retention and the inability to form complexes with other signaling partners such as the phosphorylated form of STAT-5. Furthermore, this isoform creates heterodimers and acts as a dominant negative regulator of GR function that
leads to a poor response to corticosteroids [4,5]. Considering the important role that the GR plays in hematopoiesis, Varricchio et al. and Poletto et al. searched for correlations between the A3669G SNP and MPNs. They found indeed a positive association between this SNP, and PV and PMF, respectively [4,6]. We aimed to explore this hypothesis on a large cohort of Romanian patients with MPNs – PV, ET and PMF. The study was based on a case-control design with two groups. The first one consists of 388 MPNs patients divided as follows: 170 with ET, 161 with PV and 57 with PMF. A total of 138 patients with PV (86%), 94 patients with ET (55%), and 25 patients with PMF (44%) were positive for JAK2 V617F mutation. The CALR indels characterized 35 patients with ET (21%) and 17 patients with PMF (30%). MPL mutations were rare events, seen in three patients with ET (1.8%) and two patients with PMF (3.5%). The diagnosis of all the MPN patients was reviewed according to the 2008 WHO classification of the myeloid neoplasms [7]. The control group consisted in 448 individuals age- and sex-matched to the patients. The controls were free of any malignancies, including the hematological ones. The GR polymorphism was investigated using a PCR-RFLP protocol, as previously described [5,8]. The distribution of qualitative variables was compared by the Fisher ’s exact test, while the Mann-Whitney test was used to compare the medians of the quantitative variables. The study was approved by the Ethics Committee of the “Iuliu Hatieganu” University of Medicine and Pharmacy, ClujNapoca, Romania. Written consent was obtained from all the participants to the study. The G/A genotype was detected in 65 patients with PV (OR ⫽ 0.9; 95 % CI ⫽ 0.6–1.4; p ⫽ 0.8), 64 patients with ET (OR ⫽ 1; 95 % CI ⫽ 0.7–1.5; p ⫽ 0.7), and 23 patients with PMF (OR ⫽ 0.9; 95% CI ⫽ 0.5–1.5; p ⫽ 0.7), compared to 174 individuals in the control group.
Correspondence: Adrian P. Trifa, MD, PhD, Department of Medical Genetics, “Iuliu Hat ieganu” University of Medicine and Pharmacy, 6, Pasteur Street, ´ 400349, Cluj-Napoca, Romania. Tel: ⫹ 40 750 774406. Fax: ⫹ 40 264 598606. E-mail: [email protected] Received 3 March 2015; accepted 17 April 2015
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R. M. Costache et al.
Table I. Genotypes and allele frequencies for the A3669G SNP. PV group ET group PMF group MPN (all) Controls
Leuk Lymphoma Downloaded from informahealthcare.com by Nyu Medical Center on 06/21/15 For personal use only.
A3669G SNP Genotype; n (%) A/A 92 (57) G/A 65 (40) G/G 4 (3) 69 (43) G/A ⫹ G/G Total 161 (100) Allele frequency; n (%) A 249 (77) G 73 (23) Total 322 (100)
101 (59) 64 (38) 5 (3) 69 (41)
30 (53) 23 (40) 4 (7) 27 (47)
223 (57) 152 (39) 13 (4) 165 (43)
255 (57) 174 (39) 19 (4) 193 (43)
170 (100) 57 (100)
388 (100)
448 (100)
266 (78) 83 (73) 74 (22) 31 (27) 340 (100) 114 (100)
598 (77) 178 (23) 776 (100)
684 (76) 212 (24) 896 (100)
The G/G genotype was observed in four patients with PV (OR ⫽ 1.7; 95 % CI ⫽ 0.5–5.1; p ⫽ 0.4), five patients with ET (OR ⫽ 1.5; 95% CI ⫽ 0.5–4.1; p ⫽ 0.4), and four patients with PMF (OR ⫽ 0.5; 95% CI ⫽ 0.17–1.7; p ⫽ 0.3), compared to 19 individuals from the control group. We also analyzed the combined variant genotypes (G/A ⫹ G/G), again without reaching statistical significance (p ⫽ 1 for PV, 0.58 for ET, 0.5 for PMF and 0.88 for the whole MPN cohort). Thus, the G allele had a similar frequency in patients with MPN and controls (p ⫽ 0.75 for PV, 0.49 for ET, 0.41 for PMF, and 0.7 for the whole MPN cohort). To determine whether the G allele favored the acquisition of JAK2 V617F mutation, we analyzed the frequency of GR SNP genotypes and of G allele in patients stratified after the JAK2 V617F genotype. The A3669G SNP was not enriched in JAK2 V617F-positive versus JAK2 V617F-negative patients (OR ⫽ 1.1; 95% CI ⫽ 0.72–1.7; p ⫽ 0.6). Also when comparing the JAK2 V617F-positive patients and controls, we observed a similar distribution of the A3669G SNP. The G allele was also similarly distributed between JAK2 V617F-positive and JAK2 V617F-negative patients (p ⬎ 0.5). Regarding the CALR mutation status in patients with ET and PMF, the G/A and G/G genotypes of the A3669G were similarly distributed in patients with and without CALR indels (OR ⫽ 1; 95% CI ⫽ 0.5–1.8; p ⫽ 1), and also in patients with CALR indels patients versus controls (OR ⫽ 1; 95% CI ⫽ 0.6–1.8; p ⫽ 0.8). We also attempted to establish the relationship between the A3669G SNP and laboratory (hemoglobin, white blood cells and the platelets at diagnosis) and clinical (thrombosis and splenomegaly) parameters. None of these parameters was associated with the A3669G SNP (p ⬎ 0.05 for all comparisons in all three diseases). Genotypes and allele frequencies of the GR A3669G SNP in our population of patients with MPNs and the control group are listed in detail in Table I. Among all the correlations that were performed, none reached statistical significance. Our findings showed that A3669G SNP of the GR is not implicated in the occurrence of PV, ET or PMF, regardless of the mutation status (e.g. JAK2 V617F or CALR). Varrichio et al. analyzed the GR A3669G SNP in 57 MPN patients (22 PV, 15 ET and 20 PMF) and 22 controls. Real time PCR was used to measure the JAK2 V617F mutation, while GR SNP was determined with single-strand conformation polymorphism (SSCP). They also performed mRNA isolation, Western blot and immune precipitation analyses on the erythroblasts expansion
cultures of mononuclear cells from 19 healthy donors and 16 patients with PV. Their results show that A3669G polymorphism had greater frequency in PV (55%, p ⫽ 0.0028) and PMF (35%) patients than in controls (9%) or patients with ET (6%). Regarding the PV cell culture, they obtained a great number of immature erythroblasts with low levels of GR β-globin indifferent for dexamethasone stimulation. Further, the levels of GRβ expressed by erythroblasts from four PV patients and four controls were compared by quantitative RT-PCR and the outcomes were increased 3 times for PV patients (p ⬍ 0.001) [4]. A study of 58 Diamond-Blackfan anemia patients led also by Varrichio et al., demonstrated a correlation between this GR SNP and this rare congenital form of red cell aplasia [5]. Poletto et al. investigated the frequency of GR polymorphism and its impact on disease phenotype and progression in 499 patients with PMF. They also took into account other factors such as white blood cell count, percentage of blasts, and IPSS prognostic score. The results show that the G allele occurred significantly more frequently in PMF patients (26.2%) compared with 111 healthy volunteers (18.2%; OR, 1.62; 95% CI, 1.12–2.34; p ⫽ 0.009). The G/G genotype was associated with higher WBC count, splenomegaly, higher frequency of circulating CD34 ⫹ cells at diagnosis and also with shorter overall survival (77.6 vs. 298 months, p ⫽ 0.049) and blast transformation-free survival (76.7 vs. 261 months; p ⫽ 0.018). The correlation remained significant after correction for the JAK2 V617F genotype [6]. Interestingly, positive associations between the same GR SNP and several diseases, such as: lupus erythematosus (27%), rheumatoid arthritis (42%) or central adiposity (30%), were found in the past, suggesting that this SNP has consequences in several various metabolic pathways [3]. In conclusion, we were not able to replicate the positive association between the GR A3669G SNP and MPNs, seen in previous studies. In our large cohort of patients with PV, ET and PMF, this SNP had a similar distribution as in the general population. This was also the case for the molecular subtypes of the MPN (e.g. JAK2 V617F and CALR mutated).
Acknowledgements This study would have not been possible without the help of our colleague and friend Dr Andrei Cucuianu. Unfortunately, he passed away while the study was in progress. The study was supported by Internal Research Grants from the Universities of Medicine and Pharmacy Cluj-Napoca and Tîrgu-Mures to RMC (grant number 1493/2/28.01.2014) and ´ CB (grant number 1/30.01.2013). Potential conflict of interest: Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.
References [1] Cazzola M, Kralovics R. From Janus kinase 2 to calreticulin: the clinically relevant genomic landscape of myeloproliferative neoplasms. Blood 2014;123:3714–3719.
GR A3669G SNP in MPN
Leuk Lymphoma Downloaded from informahealthcare.com by Nyu Medical Center on 06/21/15 For personal use only.
[2] Chang TJ, Scher BM, Waxman S, et al. Inhibition of mouse GATA-1 function by the glucocorticoid receptor: possible mechanism of steroid inhibition of erythroleukemia cell differentiation. Mol Endocrinol 1993;7:528–542. [3] Varricchio L, Migliaccio AR. The role of glucocorticoid receptor (GR) polymorphisms in human erythropoiesis. Am J Blood Res 2014;4:53–72. [4] Varricchio L, Masselli E, Alfani E, et al. The dominant negative β isoform of the glucocorticoid receptor is uniquely expressed in erythroid cells expanded from polycythemia vera patients. Blood 2011;118:425–436. [5] Varricchio L, Godbold J, Scott SA , et al. Increased frequency of the glucocorticoid receptor A3669G (rs6198) polymorphism in patients with Diamond-Blackfan anemia. Blood 2011;118:473–474.
3
[6] Poletto V, Rosti V, Villani L, et al. A3669G polymorphism of glucocorticoid receptor is a susceptibility allele for primary myelofibrosis and contributes to phenotypic diversity and blast transformation. Blood 2012;120:3112–3117. [7] Tefferi A , Vardiman JW. Classification and diagnosis of myeloproliferative neoplasms: the 2008 World Health Organization criteria and point-of-care diagnostic algorithms. Leukemia 2008;22: 14–22. [8] Derijk RH, Schaaf MJ, Turner G, et al. A human glucocorticoid receptor gene variant that increases the stability of the glucocorticoid receptor beta-isoform mRNA is associated with rheumatoid arthritis. J Rheumatol 2001;28:2383–2388.
