2026-06-30 | Treatment of polycythemia vera in children

Introduction. Polycythemia vera (PV) is a Philadelphia chromosome (Ph)-negative myeloproliferative neoplasm that is extremely rare in childhood. Currently, there are no reliable data on the efficacy and tolerability of cytoreductive therapy in children with PV. The aim of the study is to evaluate the clinical and hematological and molecular response, as well as the tolerability of cytoreductive therapy in patients under 18 years of age with PV. Materials and methods. The Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology has developed its own management strategy for patients with PV: cytoreductive therapy is administered in the presence of a driver mutation in the JAK2V617F gene, JAK2 exon 12, and/or microcirculatory disorders with von Willebrand factor deficiency, or in the absence of an effect from antiplatelet agents in patients with microcirculatory disorders, or in patients with hemorrhagic syndrome and acquired von Willebrand factor deficiency. A total of 48 patients were included in the study (35 boys and 13 girls). The median follow-up period was 2.3 (2.0–3.7) years. The median age at diagnosis was 14.9 (9.0–16.8) years. The JAK2V617F mutation was found in 30 (62.5%) patients, the JAK2 exon 12 mutation – in 3 (6.25%) patients, and 15 (31.25%) patients were JAK2-negative. Cytoreductive therapy was administered to 28 (58%) patients. Results. The majority of patients achieved a partial clinical and hematological response in the first year of treatment: 21/25 (84.0%) patients in the group treated with interferon and 7/8 (87.5%) in the group treated with hydroxycarbamide. In the interferon group, a partial molecular response was registered in 12/17 (70.5%) patients; 5/17 (29.5%) patients showed no molecular response. The median JAK2V617F/JAK2 exon 12 allele burden decreased from 24% (17–30%) to 15% (9–22%) (z = 3.5; p 0.001). In the hydroxycarbamide group, the allele burden did not change significantly in any of the 7 (100%) patients (p = 0.916). Conclusion. Our findings support further investigation of interferons as a preferred cytoreductive treatment option in children and adolescents with PV.

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2026-06-24 | Glucose transport dependency defines a therapeutic vulnerability in JAK2V617F-driven myeloproliferative neoplasms.

Myeloproliferative neoplasms (MPN) comprise a heterogenous group of hematological malignancies that include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). Current therapeutic strategies rely on cytoreductive approaches that mitigate disease burden and thromboembolic risk but are not curative. Allogeneic stem cell transplantation remains the only curative option, underscoring the need for novel therapeutic strategies. We previously identified hypoxia-inducible factor 1 (HIF-‍‍1) as a selective vulnerability in JAK2V617F-positive cells, but the underlying metabolic mechanisms remain incompletely defined. In vitro studies utilized 32D cells transduced with an empty vector control, Jak2WT, or Jak2V617F. To evaluate metabolic dependencies, CRISPR-Cas9 was used to generate Slc2a1 (GLUT1) and Slc2a3 (GLUT3) knockout clones, which were subsequently characterized via RNA sequencing, extracellular flux analysis, and cellular fitness assays (proliferation, viability, and apoptosis). Pharmacological targeted inhibition of GLUT1/3 was evaluated in human JAK2V617F-mutated post-MPN AML cell lines (SET-2, HEL), primary patient-derived cells and a Jak2V617F knock-in mouse model. Combinatorial efficacy was assessed using the JAK1/2 inhibitor ruxolitinib. JAK2V617F induced HIF-1-dependent metabolic reprogramming, characterized by increased glycolytic flux and oxidative metabolism. Complete abrogation of glucose uptake occurred only upon combined loss of GLUT1 and GLUT3 in Jak2V617F cells, revealing functional redundancy between these transporters that sustains enhanced glycolysis. Disruption of glucose uptake selectively induced stress-associated transcriptional programs and replication stress, triggering an S-phase arrest that culminated in apoptosis and impaired viability, specifically in Jak2V617F cells. In vivo, pharmacological inhibition of HIF-1 or GLUT induced a reorganization of erythropoiesis to the spleen but did not ameliorate core disease features. In contrast, in vitro GLUT inhibition robustly reduced cell viability in human SET-2 and HEL cell lines and impaired proliferation, viability, and colony formation in patient-derived PBMCs. Collectively, these findings establish HIF-1-driven glucose metabolism as a metabolic vulnerability in JAK2V617F-positive MPN. The selective exhaustion of patient-derived clones defines the HIF-1-GLUT1/3 axis as a central, targetable bottleneck. These data provide a mechanistic rationale for further investigation of HIF-1 or GLUT inhibitors, suggesting that targeting this fundamental requirement may help overcome clinical limitations to achieve disease modification and eradicate the malignant clone.

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2026-06-20 | Hydroxyurea-associated digital gangrene: a case report and narrative review of reported cases and emerging pathophysiology.

Hydroxyurea (HU) is a first-line oral cytoreductive agent for selected patients with myeloproliferative neoplasms (MPNs), including polycythemia vera (PV), due to its efficacy and tolerability. Although cutaneous ulceration is a recognized complication of long-term HU exposure, HU-associated digital gangrene is rare, and upper-extremity involvement in PV has not previously been reported. We describe the first case of HU-associated digital gangrene in a patient with PV. A 72-year-old man with well-controlled Janus kinase 2 (JAK2)-positive PV, treated with HU for more than a decade, developed painless dry gangrene of the right index and middle fingers. Vascular imaging showed no significant arterial occlusion or embolic source. Hematologic parameters remained within target ranges, and the workup for autoimmune disease, infection, and hypercoagulability was unremarkable. HU was discontinued, and the ischemia stabilized without surgical intervention. With no alternative etiology identified, delayed HU-associated vasculopathy was suspected. Our literature review identified three previously reported cases of HU-associated digital gangrene, though limited to the lower extremities - two in chronic myeloid leukemia (CML) and one in sickle cell disease (SCD). In each case, gangrene developed after prolonged HU exposure, alternative etiologies were not substantiated, and stabilization or clinical improvement followed HU withdrawal. The present case aligns with this pattern while extending the reported phenotype to well-controlled PV and upper-extremity digits. Given the small number of reported cases, the pathophysiology remains incompletely defined and is largely extrapolated from studies of more frequently described HU-associated ulceration, histopathologic reports of HU-related tissue injury, and in vitro studies of HU effects on endothelial and circulating cells. Plausible mechanisms include cumulative endothelial injury, localized thrombo-occlusive microvascular dysfunction, impaired vascular and cutaneous repair, and interaction with PV-related microvascular susceptibility. Clinicians should include HU-associated vasculopathy in the differential diagnosis of otherwise unexplained digital ischemia, as prompt drug cessation may limit progression and improve digit salvage.

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