Idiopathic erythrocytosis: a germline disease?. Elli, E. M., Mauri, M., D’Aliberti, D., Crespiatico, I., Fontana, D., Redaelli, S., Pelucchi, S., Spinelli, S., Manghisi, B., Cavalca, F., Aroldi, A., Ripamonti, A., Ferrari, S., Palamini, S., Mottadelli, F., Massimino, L., Ramazzotti, D., Cazzaniga, G., Piperno, A., Gambacorti-Passerini, C., & Piazza, R. Clinical and Experimental Medicine, 24(1):11, January, 2024. ![Idiopathic erythrocytosis: a germline disease? [link]](https://bibbase.org/img/filetypes/link.svg "link")
Paper doi abstract bibtex Polycythemia Vera (PV) is typically caused by V617F or exon 12 JAK2 mutations. Little is known about Polycythemia cases where no JAK2 variants can be detected, and no other causes identified. This condition is defined as idiopathic erythrocytosis (IE). We evaluated clinical-laboratory parameters of a cohort of 56 IE patients and we determined their molecular profile at diagnosis with paired blood/buccal-DNA exome-sequencing coupled with a high-depth targeted OncoPanel to identify a possible underling germline or somatic cause. We demonstrated that most of our cohort (40/56: 71.4%) showed no evidence of clonal hematopoiesis, suggesting that IE is, in large part, a germline disorder. We identified 20 low mutation burden somatic variants (Variant allelic fraction, VAF, \textless 10%) in only 14 (25%) patients, principally involving DNMT3A and TET2. Only 2 patients presented high mutation burden somatic variants, involving DNMT3A, TET2, ASXL1 and WT1. We identified recurrent germline variants in 42 (75%) patients occurring mainly in JAK/STAT, Hypoxia and Iron metabolism pathways, among them: JAK3-V722I and HIF1A-P582S; a high fraction of patients (48.2%) resulted also mutated in homeostatic iron regulatory gene HFE-H63D or C282Y. By generating cellular models, we showed that JAK3-V722I causes activation of the JAK-STAT5 axis and upregulation of EPAS1/HIF2A, while HIF1A-P582S causes suppression of hepcidin mRNA synthesis, suggesting a major role for these variants in the onset of IE.
@article{elli_idiopathic_2024,
title = {Idiopathic erythrocytosis: a germline disease?},
volume = {24},
issn = {1591-9528},
shorttitle = {Idiopathic erythrocytosis},
url = {https://doi.org/10.1007/s10238-023-01283-y},
doi = {10.1007/s10238-023-01283-y},
abstract = {Polycythemia Vera (PV) is typically caused by V617F or exon 12 JAK2 mutations. Little is known about Polycythemia cases where no JAK2 variants can be detected, and no other causes identified. This condition is defined as idiopathic erythrocytosis (IE). We evaluated clinical-laboratory parameters of a cohort of 56 IE patients and we determined their molecular profile at diagnosis with paired blood/buccal-DNA exome-sequencing coupled with a high-depth targeted OncoPanel to identify a possible underling germline or somatic cause. We demonstrated that most of our cohort (40/56: 71.4\%) showed no evidence of clonal hematopoiesis, suggesting that IE is, in large part, a germline disorder. We identified 20 low mutation burden somatic variants (Variant allelic fraction, VAF, {\textless} 10\%) in only 14 (25\%) patients, principally involving DNMT3A and TET2. Only 2 patients presented high mutation burden somatic variants, involving DNMT3A, TET2, ASXL1 and WT1. We identified recurrent germline variants in 42 (75\%) patients occurring mainly in JAK/STAT, Hypoxia and Iron metabolism pathways, among them: JAK3-V722I and HIF1A-P582S; a high fraction of patients (48.2\%) resulted also mutated in homeostatic iron regulatory gene HFE-H63D or C282Y. By generating cellular models, we showed that JAK3-V722I causes activation of the JAK-STAT5 axis and upregulation of EPAS1/HIF2A, while HIF1A-P582S causes suppression of hepcidin mRNA synthesis, suggesting a major role for these variants in the onset of IE.},
language = {en},
number = {1},
urldate = {2024-01-24},
journal = {Clinical and Experimental Medicine},
author = {Elli, E. M. and Mauri, M. and D’Aliberti, D. and Crespiatico, I. and Fontana, D. and Redaelli, S. and Pelucchi, S. and Spinelli, S. and Manghisi, B. and Cavalca, F. and Aroldi, A. and Ripamonti, A. and Ferrari, S. and Palamini, S. and Mottadelli, F. and Massimino, L. and Ramazzotti, D. and Cazzaniga, G. and Piperno, A. and Gambacorti-Passerini, C. and Piazza, R.},
month = jan,
year = {2024},
keywords = {DDM, Erythropoiesis, Idiopathic erythrocytosis, MYS, Myeloid Neoplasia, Myeloid Solution, NGS sequencing},
pages = {11},
}
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This condition is defined as idiopathic erythrocytosis (IE). We evaluated clinical-laboratory parameters of a cohort of 56 IE patients and we determined their molecular profile at diagnosis with paired blood/buccal-DNA exome-sequencing coupled with a high-depth targeted OncoPanel to identify a possible underling germline or somatic cause. We demonstrated that most of our cohort (40/56: 71.4%) showed no evidence of clonal hematopoiesis, suggesting that IE is, in large part, a germline disorder. We identified 20 low mutation burden somatic variants (Variant allelic fraction, VAF, \\textless 10%) in only 14 (25%) patients, principally involving DNMT3A and TET2. Only 2 patients presented high mutation burden somatic variants, involving DNMT3A, TET2, ASXL1 and WT1. We identified recurrent germline variants in 42 (75%) patients occurring mainly in JAK/STAT, Hypoxia and Iron metabolism pathways, among them: JAK3-V722I and HIF1A-P582S; a high fraction of patients (48.2%) resulted also mutated in homeostatic iron regulatory gene HFE-H63D or C282Y. By generating cellular models, we showed that JAK3-V722I causes activation of the JAK-STAT5 axis and upregulation of EPAS1/HIF2A, while HIF1A-P582S causes suppression of hepcidin mRNA synthesis, suggesting a major role for these variants in the onset of IE.","language":"en","number":"1","urldate":"2024-01-24","journal":"Clinical and Experimental Medicine","author":[{"propositions":[],"lastnames":["Elli"],"firstnames":["E.","M."],"suffixes":[]},{"propositions":[],"lastnames":["Mauri"],"firstnames":["M."],"suffixes":[]},{"propositions":[],"lastnames":["D’Aliberti"],"firstnames":["D."],"suffixes":[]},{"propositions":[],"lastnames":["Crespiatico"],"firstnames":["I."],"suffixes":[]},{"propositions":[],"lastnames":["Fontana"],"firstnames":["D."],"suffixes":[]},{"propositions":[],"lastnames":["Redaelli"],"firstnames":["S."],"suffixes":[]},{"propositions":[],"lastnames":["Pelucchi"],"firstnames":["S."],"suffixes":[]},{"propositions":[],"lastnames":["Spinelli"],"firstnames":["S."],"suffixes":[]},{"propositions":[],"lastnames":["Manghisi"],"firstnames":["B."],"suffixes":[]},{"propositions":[],"lastnames":["Cavalca"],"firstnames":["F."],"suffixes":[]},{"propositions":[],"lastnames":["Aroldi"],"firstnames":["A."],"suffixes":[]},{"propositions":[],"lastnames":["Ripamonti"],"firstnames":["A."],"suffixes":[]},{"propositions":[],"lastnames":["Ferrari"],"firstnames":["S."],"suffixes":[]},{"propositions":[],"lastnames":["Palamini"],"firstnames":["S."],"suffixes":[]},{"propositions":[],"lastnames":["Mottadelli"],"firstnames":["F."],"suffixes":[]},{"propositions":[],"lastnames":["Massimino"],"firstnames":["L."],"suffixes":[]},{"propositions":[],"lastnames":["Ramazzotti"],"firstnames":["D."],"suffixes":[]},{"propositions":[],"lastnames":["Cazzaniga"],"firstnames":["G."],"suffixes":[]},{"propositions":[],"lastnames":["Piperno"],"firstnames":["A."],"suffixes":[]},{"propositions":[],"lastnames":["Gambacorti-Passerini"],"firstnames":["C."],"suffixes":[]},{"propositions":[],"lastnames":["Piazza"],"firstnames":["R."],"suffixes":[]}],"month":"January","year":"2024","keywords":"DDM, Erythropoiesis, Idiopathic erythrocytosis, MYS, Myeloid Neoplasia, Myeloid Solution, NGS sequencing","pages":"11","bibtex":"@article{elli_idiopathic_2024,\n\ttitle = {Idiopathic erythrocytosis: a germline disease?},\n\tvolume = {24},\n\tissn = {1591-9528},\n\tshorttitle = {Idiopathic erythrocytosis},\n\turl = {https://doi.org/10.1007/s10238-023-01283-y},\n\tdoi = {10.1007/s10238-023-01283-y},\n\tabstract = {Polycythemia Vera (PV) is typically caused by V617F or exon 12 JAK2 mutations. Little is known about Polycythemia cases where no JAK2 variants can be detected, and no other causes identified. This condition is defined as idiopathic erythrocytosis (IE). We evaluated clinical-laboratory parameters of a cohort of 56 IE patients and we determined their molecular profile at diagnosis with paired blood/buccal-DNA exome-sequencing coupled with a high-depth targeted OncoPanel to identify a possible underling germline or somatic cause. We demonstrated that most of our cohort (40/56: 71.4\\%) showed no evidence of clonal hematopoiesis, suggesting that IE is, in large part, a germline disorder. We identified 20 low mutation burden somatic variants (Variant allelic fraction, VAF, {\\textless} 10\\%) in only 14 (25\\%) patients, principally involving DNMT3A and TET2. Only 2 patients presented high mutation burden somatic variants, involving DNMT3A, TET2, ASXL1 and WT1. 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