Increased TIM-3 and galectin-9 serum levels in patients with advanced systemic mastocytosis.

BACKGROUND: Systemic mastocytosis is characterized by expansion of clonal mast cells in various tissues. Several biomarkers with diagnostic and therapeutic potential have recently been characterized in mastocytosis, such as the serum marker tryptase and the immune checkpoint molecule PD-L1. OBJECTIVE: We aimed to investigate whether serum levels of other checkpoint molecules are altered in systemic mastocytosis and whether these proteins are expressed in mastocytosis infiltrates in the bone marrow. METHODS: Levels of different checkpoint molecules were analyzed in serum of patients with different categories of systemic mastocytosis and healthy controls and correlated to disease severity. Bone marrow biopsies from patients with systemic mastocytosis were stained to confirm expression. RESULTS: Serum levels of TIM-3 and galectin-9 were increased in systemic mastocytosis, particularly in advanced subtypes, compared with healthy controls. TIM-3 and galectin-9 levels were also found to correlate with other biomarkers of systemic mastocytosis, such as serum tryptase and KIT D816V variant allele frequency in the peripheral blood. Moreover, we observed expression of TIM-3 and galectin-9 in mastocytosis infiltrates in bone marrow. CONCLUSIONS: Together, our results demonstrate for the first time that serum levels of TIM-3 and galectin-9 are increased in advanced systemic mastocytosis. Moreover, TIM-3 and galectin-9 are expressed in bone marrow infiltrates in mastocytosis. These findings provide a rationale for exploring TIM-3 and galectin-9 as diagnostic markers and eventually therapeutic targets in systemic mastocytosis, particularly in advanced forms.

[Myeloproliferative neoplasms - Update on diagnosis and treatment]. / Myeloproliferative Neoplasien: Update zu Diagnostik und Therapie.

Myeloproliferative neoplasms - Update on diagnosis and treatment Abstract. Myeloproliferative neoplasms are hematopoietic stem cell disorders presenting as chronic leukemias with excessive production of mature, myeloid blood cells. Driver mutations in JAK2, CALR or MPL mediate constitutive activation of JAK2 signaling, a common hallmark of the classical Philadelphia chromosome-negative MPN including polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF). Dysregulated hematopoiesis primarily presents with polyglobulia in PV, thrombocytosis in ET and progressive bone marrow fibrosis and increased, atypical megakaryocytes in PMF. The molecular characterization of MPNs has advanced our understanding of their pathogenesis and has facilitated diagnosis. Implementation of genetic markers enables improved prognostication, particularly in myelofibrosis. In recent years, we have seen an encouraging increase in therapeutic options for MPN including the approval of a first JAK inhibitor now followed by other agents of this class, as well as refined forms of interferon alpha. Combination therapies as well as novel therapeutic approaches are increasingly studied and hold promise for the future. Hematopoietic stem cell transplantation, which is still the only treatment option with a curative potential, is increasingly available also for elderly patients with MPN.

JAK2 exon 12 mutant mice display isolated erythrocytosis and changes in iron metabolism favoring increased erythropoiesis.

Mutations in JAK2 exon 12 are frequently found in patients with polycythemia vera (PV) that do not carry a JAK2-V617F mutation. The majority of these patients display isolated erythrocytosis. We generated a mouse model that expresses JAK2-N542-E543del, the most frequent JAK2 exon 12 mutation found in PV patients. Mice expressing the human JAK2-N542-E543del (Ex12) showed a strong increase in red blood cell parameters but normal neutrophil and platelet counts, and reduced overall survival. Erythropoiesis was increased in the bone marrow and spleen, with normal megakaryopoiesis and absence of myelofibrosis in histopathology. Erythroid progenitors and precursors were increased in hematopoietic tissues, but the numbers of megakaryocytic precursors were unchanged. Phosphorylation Stat3 and Erk1/2 proteins were increased, and a trend toward increased phospho-Stat5 and phospho-Stat1 was noted. However, Stat1 knock out in Ex12 mice induced no changes in platelet or red cell parameters, indicating that Stat1 does not play a central role in mediating the effects of Ex12 signaling on megakaryopoiesis or erythropoiesis. Ex12 mice showed decreased expression of hepcidin and increased expression of transferrin receptor-1 and erythroferrone, suggesting that the strong erythroid phenotype in Ex12 mutant mice is favored by changes in iron metabolism that optimize iron availability to allow maximal production of red cells.

Amotosalen/ultraviolet A pathogen inactivation technology reduces platelet activatability, induces apoptosis and accelerates clearance.

Amotosalen and ultraviolet A (UVA) photochemical-based pathogen reduction using the Intercept™ Blood System (IBS) is an effective and established technology for platelet and plasma components, which is adopted in more than 40 countries worldwide. Several reports point towards a reduced platelet function after Amotosalen/UVA exposure. The study herein was undertaken to identify the mechanisms responsible for the early impairment of platelet function by the IBS. Twenty-five platelet apheresis units were collected from healthy volunteers following standard procedures and split into 2 components, 1 untreated and the other treated with Amotosalen/UVA. Platelet impedance aggregation in response to collagen and thrombin was reduced by 80% and 60%, respectively, in IBS-treated units at day 1 of storage. Glycoprotein Ib (GpIb) levels were significantly lower in IBS samples and soluble glycocalicin correspondingly augmented; furthermore, GpIbα was significantly more desialylated as shown by Erythrina Cristagalli Lectin (ECL) binding. The pro-apoptotic Bak protein was significantly increased, as well as the MAPK p38 phosphorylation and caspase-3 cleavage. Stored IBS-treated platelets injected into immune-deficient nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice showed a faster clearance. We conclude that the IBS induces platelet p38 activation, GpIb shedding and platelet apoptosis through a caspase-dependent mechanism, thus reducing platelet function and survival. These mechanisms are of relevance in transfusion medicine, where the IBS increases patient safety at the expense of platelet function and survival.

Genetic studies reveal an unexpected negative regulatory role for Jak2 in thrombopoiesis.

JAK inhibitor treatment is limited by the variable development of anemia and thrombocytopenia thought to be due to on-target JAK2 inhibition. We evaluated the impact of Jak2 deletion in platelets (PLTs) and megakaryocytes (MKs) on blood counts, stem/progenitor cells, and Jak-Stat signaling. Pf4-Cre-mediated Jak2 deletion in PLTs and MKs did not compromise PLT formation but caused thrombocytosis, and resulted in expansion of MK progenitors and Lin(-)Sca1(+)Kit+ cells. Serum thrombopoietin (TPO) was maintained at normal levels in Pf4-Cre-positive Jak2(f/f) mice, consistent with reduced internalization/turnover by Jak2-deficient PLTs. These data demonstrate that Jak2 in terminal megakaryopoiesis is not required for PLT production, and that Jak2 loss in PLTs and MKs results in non-autonomous expansion of stem/progenitors and of MKs and PLTs via dysregulated TPO turnover. This suggests that the thrombocytopenia frequently seen with JAK inhibitor treatment is not due to JAK2 inhibition in PLTs and MKs, but rather due to JAK2 inhibition in stem/progenitor cells.

Translational implications of somatic genomics in acute myeloid leukaemia.

SUMMARY: Acute myeloid leukaemia (AML) is caused by acquired somatic mutations in haemopoietic progenitors. Understanding of the genetic basis of the disease has greatly benefited from the use of DNA sequencing to identify novel disease alleles. Chromosomal aberrations are known to drive AML and are the mainstay of risk classification. Mutations in FLT3, NPM1, and CEBPA provide prognostic information and have been integrated into clinical diagnostics and clinical practice. Comprehensive next-generation sequencing studies have given insight into AML pathogenesis. These insights are leading to refined prognostic stratification and suggest differentially tailored treatment based on integrated genetic profiles. Translation of comprehensive genetic analyses to the clinical setting is the next challenge, to enable genotype-specific therapies for patients with AML and other malignant disorders.

Hemostasis and complement in allogeneic hematopoietic stem cell transplantation: clinical significance of two interactive systems.

Hematopoietic stem cell transplantation (HCT) represents a curative treatment option for certain malignant and nonmalignant hematological diseases. Conditioning regimens before HCT, the development of graft-versus-host disease (GVHD) in the allogeneic setting, and delayed immune reconstitution contribute to early and late complications by inducing tissue damage or humoral alterations. Hemostasis and/or the complement system are biological regulatory defense systems involving humoral and cellular reactions and are variably involved in these complications after allogeneic HCT. The hemostasis and complement systems have multiple interactions, which have been described both under physiological and pathological conditions. They share common tissue targets, such as the endothelium, which suggests interactions in the pathogenesis of several serious complications in the early or late phase after HCT. Complications in which both systems interfere with each other and thus contribute to disease pathogenesis include transplant-associated thrombotic microangiopathy (HSCT-TMA), sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD), and GVHD. Here, we review the current knowledge on changes in hemostasis and complement after allogeneic HCT and how these changes may define clinical impact.

Development of Resistance to Type II JAK2 Inhibitors in MPN Depends on AXL Kinase and Is Targetable.

PURPOSE: Myeloproliferative neoplasms (MPN) dysregulate JAK2 signaling. Because clinical JAK2 inhibitors have limited disease-modifying effects, type II JAK2 inhibitors such as CHZ868 stabilizing inactive JAK2 and reducing MPN clones, gain interest. We studied whether MPN cells escape from type ll inhibition. EXPERIMENTAL DESIGN: MPN cells were continuously exposed to CHZ868. We used phosphoproteomic analyses and ATAC/RNA sequencing to characterize acquired resistance to type II JAK2 inhibition, and targeted candidate mediators in MPN cells and mice. RESULTS: MPN cells showed increased IC50 and reduced apoptosis upon CHZ868 reflecting acquired resistance to JAK2 inhibition. Among >2,500 differential phospho-sites, MAPK pathway activation was most prominent, while JAK2-STAT3/5 remained suppressed. Altered histone occupancy promoting AP-1/GATA binding motif exposure associated with upregulated AXL kinase and enriched RAS target gene profiles. AXL knockdown resensitized MPN cells and combined JAK2/AXL inhibition using bemcentinib or gilteritinib reduced IC50 to levels of sensitive cells. While resistant cells induced tumor growth in NOD/SCID gamma mice despite JAK2 inhibition, JAK2/AXL inhibition largely prevented tumor progression. Because inhibitors of MAPK pathway kinases such as MEK are clinically used in other malignancies, we evaluated JAK2/MAPK inhibition with trametinib to interfere with AXL/MAPK-induced resistance. Tumor growth was halted similarly to JAK2/AXL inhibition and in a systemic cell line-derived mouse model, marrow infiltration was decreased supporting dependency on AXL/MAPK. CONCLUSIONS: We report on a novel mechanism of AXL/MAPK-driven escape from type II JAK2 inhibition, which is targetable at different nodes. This highlights AXL as mediator of acquired resistance warranting inhibition to enhance sustainability of JAK2 inhibition in MPN.

Jak2V617F Reversible Activation Shows Its Essential Requirement in Myeloproliferative Neoplasms.

Gain-of-function mutations activating JAK/STAT signaling are seen in the majority of patients with myeloproliferative neoplasms (MPN), most commonly JAK2V617F. Although clinically approved JAK inhibitors improve symptoms and outcomes in MPNs, remissions are rare, and mutant allele burden does not substantively change with chronic therapy. We hypothesized this is due to limitations of current JAK inhibitors to potently and specifically abrogate mutant JAK2 signaling. We therefore developed a conditionally inducible mouse model allowing for sequential activation, and then inactivation, of Jak2V617F from its endogenous locus using a combined Dre-rox/Cre-lox dual-recombinase system. Jak2V617F deletion abrogates MPN features, induces depletion of mutant-specific hematopoietic stem/progenitor cells, and extends overall survival to an extent not observed with pharmacologic JAK inhibition, including when cooccurring with somatic Tet2 loss. Our data suggest JAK2V617F represents the best therapeutic target in MPNs and demonstrate the therapeutic relevance of a dual-recombinase system to assess mutant-specific oncogenic dependencies in vivo. SIGNIFICANCE: Current JAK inhibitors to treat myeloproliferative neoplasms are ineffective at eradicating mutant cells. We developed an endogenously expressed Jak2V617F dual-recombinase knock-in/knock-out model to investigate Jak2V617F oncogenic reversion in vivo. Jak2V617F deletion abrogates MPN features and depletes disease-sustaining MPN stem cells, suggesting improved Jak2V617F targeting offers the potential for greater therapeutic efficacy. See related commentary by Celik and Challen, p. 701. This article is featured in Selected Articles from This Issue, p. 695.

Prognostic impact of posttransplantation iron overload after allogeneic stem cell transplantation.

In patients referred for allogeneic hematopoietic stem cell transplantation (HSCT), iron overload is frequent and associated with increased morbidity and mortality. Both the evolution of iron overload after transplantation and its correlation with late posttransplantation events are unknown. We studied 290 patients undergoing myeloablative allogeneic HSCT between 2000 and 2009. Serum ferritin, transferrin saturation, transferrin, iron, and soluble transferrin receptor were determined regularly between 1 and 60 months after HSCT, and values were correlated with transplantation outcome. Ferritin levels peaked in the first 3 months posttransplantation and then decreased to normal values at 5 years. Transferrin saturation and iron behaved analogously, whereas transferrin and soluble transferrin receptor increased after an early nadir. Landmark survival analysis showed that hyperferritinemia had a detrimental effect on survival in all periods analyzed (0 to 6 months P < .001; 6 to 12 months P < .001; 1 to 2 years P = .02; 2 to 5 years P = .002). This effect was independent of red blood cell transfusion dependency and graft-versus-host disease. Similar trends were seen for other iron parameters. These data show the natural dynamics of iron parameters in the setting of allogeneic HSCT and provide evidence for a prognostic role of iron overload extending beyond the immediate posttransplantation period. Interventions to reduce excessive body iron might therefore be beneficial both before and after HSCT.

Characterization of engraftment dynamics in myelofibrosis after allogeneic hematopoietic cell transplantation including novel conditioning schemes.

Introduction: Myelofibrosis (MF) is a rare hematopoietic stem cell disorder progressing to bone marrow (BM) failure or blast phase. Allogeneic hematopoietic cell transplantation (HCT) represents a potentially curative therapy for a limited subset of patients with advanced MF, who are eligible, but engraftment in MF vs. AML is delayed which promotes complications. As determinants of engraftment in MF are incompletely characterized, we studied engraftment dynamics at our center. Methods: A longitudinal cohort of 71 allogeneic HCT performed 2000-2019 with >50% after 2015 was evaluated. Results: Median time to neutrophil engraftment ≥0.5x109/l was +20 days post-transplant and associated with BM fibrosis, splenomegaly and infused CD34+ cell number. Engraftment dynamics were similar in primary vs. secondary MF and were independent of MF driver mutations in JAK2, CALR and MPL. Neutrophil engraftment occurred later upon haploidentical HCT with thiotepa-busulfan-fludarabine conditioning, post-transplant cyclophosphamide and G-CSF (TBF-PTCy/G-CSF) administered to 9.9% and 15.6% of patients in 2000-2019 and after 2015, respectively. Engraftment of platelets was similarly delayed, while reconstitution of reticulocytes was not affected. Conclusions: Since MF is a rare hematologic malignancy, this data from a large number of HCT for MF is essential to substantiate that later neutrophil and platelet engraftment in MF relates both to host and treatment-related factors. Observations from this longitudinal cohort support that novel conditioning schemes administered also to rare entities such as MF, require detailed evaluation in larger, multi-center cohorts to assess also indicators of long-term graft function and overall outcome in patients with this infrequent hematopoietic neoplasm undergoing allogeneic transplantation.

Co-Occurring CSF3R W791* Germline and Somatic T618I Driver Mutations Induce Early CNL and Clonal Progression to Mixed Phenotype Acute Leukemia.

Chronic neutrophilic leukemia (CNL) relates to mutational CSF3R activation with membrane proximal CSF3R mutations such as T618I as driver mutations, but the significance of truncating mutations is not clarified. In CNL, concomitant mutations promote disease progression, but insight into longitudinal acquisition is incomplete. In this study, we investigated the role of co-occurring germline and somatic CSF3R mutations in CNL, and assessed the impact of clonal evolution on transformation to acute leukemia. We employed sequential next generation sequencing and SNP array karyotyping to assess clonal evolution in CNL of early manifestation age based on a 33-year-old patient. Germline vs. somatic mutations were differentiated using a sample from the hair follicle. To investigate a potential predisposition for CNL development and progression by germline CSF3R-W791*, allelic localizations were evaluated. We detected a somatic CSF3R-T618I mutation at 46% variant allele frequency (VAF) at the time of CNL diagnosis, which co-occurred with a CSF3R-W791* truncation at 50% VAF in the germline. Evaluation of allelic localization revealed CSF3R-T618I and W791* on the same allele. A concomitant ASXL1 mutation at 39% VAF increased to 48% VAF upon transformation to mixed phenotype acute leukemia (MPAL), which has both myeloid and lymphoid features. Clonal evolution further involved expansion of the CSF3R double-mutant clone to 90% VAF via copy neutral loss of heterozygosity on chromosome 1p and the emergence of a RUNX1 mutant subclone. Allogeneic transplantation induced complete remission. This study highlights that CNL not only transforms to AML but also to MPAL. The molecular evolution is especially interesting with a CSF3R-W791* mutation in the germline and acquisition of CSF3R-T618I on the same allele compatible with increased susceptibility for mutation acquisition facilitating RUNX1-related clonal transformation.

Interferon-γ resistance and immune evasion in glioma develop via Notch-regulated co-evolution of malignant and immune cells.

Immune surveillance is critical to prevent tumorigenesis. Gliomas evade immune attack, but the underlying mechanisms remain poorly understood. We show that glioma cells can sustain growth independent of immune system constraint by reducing Notch signaling. Loss of Notch activity in a mouse model of glioma impairs MHC-I and cytokine expression and curtails the recruitment of anti-tumor immune cell populations in favor of immunosuppressive tumor-associated microglia/macrophages (TAMs). Depletion of T cells simulates Notch inhibition and facilitates tumor initiation. Furthermore, Notch-depleted glioma cells acquire resistance to interferon-γ and TAMs re-educating therapy. Decreased interferon response and cytokine expression by human and mouse glioma cells correlate with low Notch activity. These effects are paralleled by upregulation of oncogenes and downregulation of quiescence genes. Hence, suppression of Notch signaling enables gliomas to evade immune surveillance and increases aggressiveness. Our findings provide insights into how brain tumor cells shape their microenvironment to evade immune niche control.

Recent Advances in Molecular Diagnostics and Targeted Therapy of Myeloproliferative Neoplasms.

Somatic mutations in JAK2, calreticulin, and MPL genes drive myeloproliferative neoplasms (MPN), and recent technological advances have revealed a heterogeneous genomic landscape with additional mutations in MPN. These mainly affect genes involved in epigenetic regulation and splicing and are of diagnostic and prognostic value, predicting the risk of progression and informing decisions on therapeutic management. Thus, genetic testing has become an integral part of the current state-of-the-art laboratory work-up for MPN patients and has been implemented in current guidelines for disease classification, tools for prognostic risk assessment, and recommendations for therapy. The finding that JAK2, CALR, and MPL driver mutations activate JAK2 signaling has provided a rational basis for the development of targeted JAK2 inhibitor therapies and has fueled their translation into clinical practice. However, the disease-modifying potential of JAK2 inhibitors remains limited and is further impeded by loss of therapeutic responses in a substantial proportion of patients over time. Therefore, the investigation of additional molecular vulnerabilities involved in MPN pathogenesis is imperative to advance the development of new therapeutic options. Combination of novel compounds with JAK2 inhibitors are of specific interest to enhance therapeutic efficacy of molecularly targeted treatment approaches. Here, we summarize the current insights into the genetic basis of MPN, its use as a diagnostic and prognostic tool in clinical settings, and the most recent advances in targeted therapies for MPN.

Genetics of Myeloproliferative Neoplasms.

Myeloproliferative neoplasms are hematopoietic stem cell disorders based on somatic mutations in JAK2, calreticulin, or MPL activating JAK-STAT signaling. Modern sequencing efforts have revealed the genomic landscape of myeloproliferative neoplasms with additional genetic alterations mainly in epigenetic modifiers and splicing factors. High molecular risk mutations with adverse outcomes have been identified and clonal evolution may promote progression to fibrosis and acute myeloid leukemia. JAK2V617F is recurrently detected in clonal hematopoiesis of indeterminate potential with increased risk for vascular events. Insights into the genetics of myeloproliferative neoplasms has facilitated diagnosis and prognostication and poses novel candidates for targeted therapeutic intervention.

Challenges and Perspectives for Therapeutic Targeting of Myeloproliferative Neoplasms.

Myeloproliferative neoplasms (MPNs) are hematopoietic stem cell disorders with dysregulated myeloid blood cell production and propensity for transformation to acute myeloid leukemia, thrombosis, and bleeding. Acquired mutations in JAK2, MPL, and CALR converge on hyperactivation of Janus kinase 2 (JAK2) signaling as a central feature of MPN. Accordingly, JAK2 inhibitors have held promise for therapeutic targeting. After the JAK1/2 inhibitor ruxolitinib, similar JAK2 inhibitors as fedratinib are entering clinical use. While patients benefit with reduced splenomegaly and symptoms, disease-modifying effects on MPN clone size and clonal evolution are modest. Importantly, response to ruxolitinib may be lost upon treatment suggesting the MPN clone acquires resistance. Resistance mutations, as seen with other tyrosine kinase inhibitors, have not been described in MPN patients suggesting that functional processes reactivate JAK2 signaling. Compensatory signaling, which bypasses JAK2 inhibition, and other processes contribute to intrinsic resistance of MPN cells restricting efficacy of JAK2 inhibition overall. Combinations of JAK2 inhibition with pegylated interferon-α, a well-established therapy of MPN, B-cell lymphoma 2 inhibition, and others are in clinical development with the potential to enhance therapeutic efficacy. Novel single-agent approaches targeting other molecules than JAK2 are being investigated clinically. Special focus should be placed on myelofibrosis patients with anemia and thrombocytopenia, a delicate patient population at high need for options. The extending range of new treatment approaches will increase the therapeutic options for MPN patients. This calls for concomitant improvement of our insight into MPN biology to inform tailored therapeutic strategies for individual MPN patients.

Current Concepts of Pathogenesis and Treatment of Philadelphia Chromosome-Negative Myeloproliferative Neoplasms.

Philadelphia chromosome-negative myeloproliferative neoplasms are hematopoietic stem cell disorders characterized by dysregulated proliferation of mature myeloid blood cells. They can present as polycythemia vera, essential thrombocythemia, or myelofibrosis and are characterized by constitutive activation of JAK2 signaling. They share a propensity for thrombo-hemorrhagic complications and the risk of progression to acute myeloid leukemia. Attention has also been drawn to JAK2 mutant clonal hematopoiesis of indeterminate potential as a possible precursor state of MPN. Insight into the pathogenesis as well as options for the treatment of MPN has increased in the last years thanks to modern sequencing technologies and functional studies. Mutational analysis provides information on the oncogenic driver mutations in JAK2, CALR, or MPL in the majority of MPN patients. In addition, molecular markers enable more detailed prognostication and provide guidance for therapeutic decisions. While JAK2 inhibitors represent a standard of care for MF and resistant/refractory PV, allogeneic hematopoietic stem cell transplantation remains the only therapy with a curative potential in MPN so far but is reserved to a subset of patients. Thus, novel concepts for therapy are an important need, particularly in MF. Novel JAK2 inhibitors, combination therapy approaches with ruxolitinib, as well as therapeutic approaches addressing new molecular targets are in development. Current standards and recent advantages are discussed in this review.

Renal post-mortem findings in myeloproliferative and myelodysplastic/myeloproliferative neoplasms.

Myeloproliferative neoplasms (MPN) are a heterogeneous group of hematological disorders presenting with an increased proliferation in one or several hematological cell lines. Renal manifestations of MPN have not been fully characterized so far. To morphologically assess the potential renal involvement in MPN patients, we analyzed histomorphological findings of a post-mortem cohort (n = 57) with a disease history of Philadelphia-negative MPN including polycythaemia vera, primary myelofibrosis, essential thrombocythemia, or chronic myelomonocytic leukemia (CMML). Seven (12.2%) patients presented with a pattern of diffuse glomerulosclerosis not attributable to diabetic or hypertensive nephropathy. Weak C4d staining suggestive for chronic thrombotic microangiopathy (TMA) was observed in 4/7 cases. Glomerulonephritis was excluded by light microscopy and immunohistochemistry. Patients with a pattern of diffuse glomerulosclerosis did not differ from the rest of the cohort regarding MPN subtype, disease duration, age, or sex. No significant proteinuria had been observed before death. Further findings attributed to MPNs were extramedullary hematopoiesis (n = 5; 8.8%) and tumor involvement in advanced disease (n = 4; 7.0%). Other common findings included arteriolosclerosis (n = 18; 31.6%) and signs of shock (n = 8; 14.0%). To our knowledge, this study is so far the largest investigating renal findings in MPN patients. There may be a causal relationship between idiopathic diffuse glomerular sclerosis and MPN, although its clinical significance and pathophysiology remain uncertain with TMA probably being relevant in a subgroup of cases. Our findings demonstrate the spectrum of renal findings in MPN from early to terminal disease of which hematologists should be aware of in daily clinical practice.