Novel germline JAK2R715T mutation causing PV-like erythrocytosis in 3 generations. Amelioration by Ropeg-Interferon
<p>Polycythemia vera (PV) is a clonal disorder arising from the acquired somatic mutations of the <em>JAK2</em> gene, including <em>JAK2</em><sup>V617F</sup> or several others in exon 12. A 38-year-old female had a stroke...
| Main Authors: | , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
Wiley
2024
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| _version_ | 1811141332168605696 |
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| author | Song, J Lanikova, L Kim, SJ Papadopoulos, N Meznarich, J Constantinescu, SN Parsegov, B Prchal, JF Prchal, JT |
| author_facet | Song, J Lanikova, L Kim, SJ Papadopoulos, N Meznarich, J Constantinescu, SN Parsegov, B Prchal, JF Prchal, JT |
| author_sort | Song, J |
| collection | OXFORD |
| description | <p>Polycythemia vera (PV) is a clonal disorder arising from the acquired somatic mutations of the <em>JAK2</em> gene, including <em>JAK2</em><sup>V617F</sup> or several others in exon 12. A 38-year-old female had a stroke at age 32 and found to have elevated hemoglobin, normal leukocytes, normal platelets, and tested negative for <em>JAK2</em><sup>V617F</sup> and exon 12 mutations. Next generation sequencing revealed a novel mutation: <em>JAK2</em><sup>R715T</sup> in the pseudokinase domain (JH2) at 47.5%. Its presence in her nail DNA confirmed a germline origin. Her mother and her son similarly had erythrocytosis and a <em>JAK2</em><sup>R715T</sup> mutation. Computer modeling indicated gain-of-function JAK2 activity. The propositus and her mother had polyclonal myelopoiesis, ruling out another somatic mutation-derived clonal hematopoiesis. Some erythroid progenitors of all three generations grew without erythropoietin, a hallmark of PV. The <em>in vitro</em> reporter assay confirmed increased activity of the <em>JAK2</em><sup>R715T</sup> kinase. Similar to PV, the <em>JAK2</em><sup>R715T</sup> native cells have increased <em>STAT5</em> phosphorylation, augmented transcripts of prothrombotic and inflammatory genes, and decreased <em>KLF2</em> transcripts. The propositus was not controlled by hydroxyurea, and JAK2 inhibitors were not tolerated; however, Ropeginterferon-alfa-2b (Ropeg-IFN-α) induced a remission. Ropeg-IFN-α treatment also reduced JAK2 activity in the propositus, her mother and <em>JAK2</em><sup>V617F</sup> PV subjects. We report dominantly inherited erythrocytosis secondary to a novel germline <em>JAK2</em><sup>R715T</sup> gain-of-function mutation with many but not all comparable molecular features to <em>JAK2</em><sup>V617F</sup> PV. We also document a previously unreported inhibitory mechanism of JAK2 signaling by Ropeg-IFN-α.</p> |
| first_indexed | 2024-09-25T04:36:11Z |
| format | Journal article |
| id | oxford-uuid:5a1026d3-30c7-4ab6-acea-d99bb7318e9a |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-09-25T04:36:11Z |
| publishDate | 2024 |
| publisher | Wiley |
| record_format | dspace |
| spelling | oxford-uuid:5a1026d3-30c7-4ab6-acea-d99bb7318e9a2024-09-24T08:16:26ZNovel germline JAK2R715T mutation causing PV-like erythrocytosis in 3 generations. Amelioration by Ropeg-InterferonJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:5a1026d3-30c7-4ab6-acea-d99bb7318e9aEnglishSymplectic ElementsWiley2024Song, JLanikova, LKim, SJPapadopoulos, NMeznarich, JConstantinescu, SNParsegov, BPrchal, JFPrchal, JT<p>Polycythemia vera (PV) is a clonal disorder arising from the acquired somatic mutations of the <em>JAK2</em> gene, including <em>JAK2</em><sup>V617F</sup> or several others in exon 12. A 38-year-old female had a stroke at age 32 and found to have elevated hemoglobin, normal leukocytes, normal platelets, and tested negative for <em>JAK2</em><sup>V617F</sup> and exon 12 mutations. Next generation sequencing revealed a novel mutation: <em>JAK2</em><sup>R715T</sup> in the pseudokinase domain (JH2) at 47.5%. Its presence in her nail DNA confirmed a germline origin. Her mother and her son similarly had erythrocytosis and a <em>JAK2</em><sup>R715T</sup> mutation. Computer modeling indicated gain-of-function JAK2 activity. The propositus and her mother had polyclonal myelopoiesis, ruling out another somatic mutation-derived clonal hematopoiesis. Some erythroid progenitors of all three generations grew without erythropoietin, a hallmark of PV. The <em>in vitro</em> reporter assay confirmed increased activity of the <em>JAK2</em><sup>R715T</sup> kinase. Similar to PV, the <em>JAK2</em><sup>R715T</sup> native cells have increased <em>STAT5</em> phosphorylation, augmented transcripts of prothrombotic and inflammatory genes, and decreased <em>KLF2</em> transcripts. The propositus was not controlled by hydroxyurea, and JAK2 inhibitors were not tolerated; however, Ropeginterferon-alfa-2b (Ropeg-IFN-α) induced a remission. Ropeg-IFN-α treatment also reduced JAK2 activity in the propositus, her mother and <em>JAK2</em><sup>V617F</sup> PV subjects. We report dominantly inherited erythrocytosis secondary to a novel germline <em>JAK2</em><sup>R715T</sup> gain-of-function mutation with many but not all comparable molecular features to <em>JAK2</em><sup>V617F</sup> PV. We also document a previously unreported inhibitory mechanism of JAK2 signaling by Ropeg-IFN-α.</p> |
| spellingShingle | Song, J Lanikova, L Kim, SJ Papadopoulos, N Meznarich, J Constantinescu, SN Parsegov, B Prchal, JF Prchal, JT Novel germline JAK2R715T mutation causing PV-like erythrocytosis in 3 generations. Amelioration by Ropeg-Interferon |
| title | Novel germline JAK2R715T mutation causing PV-like erythrocytosis in 3 generations. Amelioration by Ropeg-Interferon |
| title_full | Novel germline JAK2R715T mutation causing PV-like erythrocytosis in 3 generations. Amelioration by Ropeg-Interferon |
| title_fullStr | Novel germline JAK2R715T mutation causing PV-like erythrocytosis in 3 generations. Amelioration by Ropeg-Interferon |
| title_full_unstemmed | Novel germline JAK2R715T mutation causing PV-like erythrocytosis in 3 generations. Amelioration by Ropeg-Interferon |
| title_short | Novel germline JAK2R715T mutation causing PV-like erythrocytosis in 3 generations. Amelioration by Ropeg-Interferon |
| title_sort | novel germline jak2r715t mutation causing pv like erythrocytosis in 3 generations amelioration by ropeg interferon |
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