Cancers · 2026
Post-Treatment Persistent Erythrocytosis in Patients with Hodgkin Lymphoma: Molecular Mechanisms Underlying the Pathogenesis of Erythrocytosis.
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Koyun Derya, Yüksel Seher, Civriz Bozdağ Sinem, Tuncalı Timur, Kuzu Işınsu, Özcan Muhit
Аннотация
BACKGROUND: Post-treatment erythrocytosis (PT-E+)-an increase in red blood cell counts after therapy-is an uncommon but reproducible finding in a subset of Hodgkin lymphoma (HL) survivors, and its biological basis remains undefined.
METHODS: A targeted DNA sequencing panel of 33 genes was used at diagnosis and during follow-up in PT-E+ patients and HL controls who did not develop erythrocytosis (E-; those without increased red blood cells). Germline (inherited) and somatic (acquired) genetic variants were compared, and changes in variant frequency over time were assessed.
RESULTS: PT-E+ patients had a unique molecular profile. They showed inherited variants in genes that regulate oxygen sensing and red blood cell production (EPAS1, EGLN3, HIF3A, PKLR, SH2B3, and RAB4B-EGLN2). Rare, acquired mutations affecting hypoxia, HIF, and EPO pathways (EGLN1/2/3, EPAS1, HIF1A/3A, VHL, EPO, and PKLR) were also found. These changes did not appear in E- controls, who instead had common clonal hematopoiesis mutations (DNMT3A, TET2, ASXL1, and JAK3). Most somatic variants in the hypoxia pathway in PT-E+ patients decreased or disappeared after treatment, which suggests these changes are temporary and influenced by the surrounding environment.
CONCLUSIONS: PT-E+ is biologically different from polycythemia vera and from idiopathic or JAK2-unmutated erythrocytosis. Both inherited risk and HL-related hypoxic or inflammatory stress are present. This supports a two-hit model, in which genetically primed red blood cell pathways respond strongly to disease-related triggers. These results suggest a new way to understand erythrocytosis after HL treatment.
METHODS: A targeted DNA sequencing panel of 33 genes was used at diagnosis and during follow-up in PT-E+ patients and HL controls who did not develop erythrocytosis (E-; those without increased red blood cells). Germline (inherited) and somatic (acquired) genetic variants were compared, and changes in variant frequency over time were assessed.
RESULTS: PT-E+ patients had a unique molecular profile. They showed inherited variants in genes that regulate oxygen sensing and red blood cell production (EPAS1, EGLN3, HIF3A, PKLR, SH2B3, and RAB4B-EGLN2). Rare, acquired mutations affecting hypoxia, HIF, and EPO pathways (EGLN1/2/3, EPAS1, HIF1A/3A, VHL, EPO, and PKLR) were also found. These changes did not appear in E- controls, who instead had common clonal hematopoiesis mutations (DNMT3A, TET2, ASXL1, and JAK3). Most somatic variants in the hypoxia pathway in PT-E+ patients decreased or disappeared after treatment, which suggests these changes are temporary and influenced by the surrounding environment.
CONCLUSIONS: PT-E+ is biologically different from polycythemia vera and from idiopathic or JAK2-unmutated erythrocytosis. Both inherited risk and HL-related hypoxic or inflammatory stress are present. This supports a two-hit model, in which genetically primed red blood cell pathways respond strongly to disease-related triggers. These results suggest a new way to understand erythrocytosis after HL treatment.