Polycythemia vera (PV) is a chronic myeloproliferative neoplasm. Virtually all PV patients are iron deficient at presentation and/or during the course of their disease. The co-existence of iron deficiency and polycythemia presents a physiological disconnect. Hepcidin, the master regulator of iron metabolism, is regulated by circulating iron levels, erythroblast secretion of erythroferrone, and inflammation. Both decreased circulating iron and increased erythroferrone levels, which occur as a consequence of erythroid hyperplasia in PV, are anticipated to suppress hepcidin and enable recovery from iron deficiency. Inflammation which accompanies PV is likely to counteract hepcidin suppression, but the relatively low serum ferritin levels observed suggest that inflammation is not a major contributor to the dysregulated iron metabolism. Furthermore, potential defects in iron absorption, aberrant hypoxia sensing and signaling, and frequency of bleeding to account for iron deficiency in PV patients have not been fully elucidated. Insufficiently suppressed hepcidin given the degree of iron deficiency in PV patients strongly suggests that disordered iron metabolism is an important component of the pathobiology of PV. Normalization of hematocrit levels using therapeutic phlebotomy is the most common approach for reducing the incidence of thrombotic complications, a therapy which exacerbates iron deficiency, contributing to a variety of non-hematological symptoms. The use of cytoreductive therapy in high-risk PV patients frequently works more effectively to reverse PV-associated symptoms in iron-deficient relative to iron-replete patients. Lastly, differences in iron-related parameters between PV patients and mice with JAK2 V617F and JAK2 exon 12 mutations suggest that specific regions in JAK2 may influence iron metabolism by nuanced changes of erythropoietin receptor signaling. In this review, we comprehensively discuss the clinical consequences of iron deficiency in PV, provide a framework for understanding the potential dysregulation of iron metabolism, and present a rationale for additional therapeutic options for iron-deficient PV patients.
Mast cell leukemia (MCL) is a rare subtype of systemic mastocytosis (SM) defined by >20% mast cells (MC) on a bone marrow aspirate. We evaluated 92 patients with MCL from the European Competence Network on Mastocytosis registry. Thirty-one (34%) patients had a diagnosis of MCL with an associated hematologic neoplasm (MCL-AHN). Chronic MCL (lack of C-findings) comprised 14% of patients, and only 4.5% had 'leukemic MCL' (≥ 10% circulating MCs). KIT D816V was found in 62/85 (73%) evaluable patients; 9 (11%) individuals exhibited alternative KIT mutations, and no KIT variants were detected in 14 (17%) subjects. Ten evaluable patients (17%) had an abnormal karyotype and the poor-risk SRSF2, ASXL1, and RUNX1 (S/A/R) mutations were identified in 16/36 (44%) patients who underwent next-generation sequencing. Midostaurin was the most common therapy, administered to 65% of patients, and 45% as first-line therapy. The median overall survival (OS) was 1.6 years. In multivariate analysis (S/A/R mutations excluded due to low event rates), a diagnosis of MCL-AHN (HR 4.7, 95% CI 1.7 - 13.0, p = 0.001) and abnormal karyotype (HR 5.6, 95% CI 1.4 - 13.3, p = 0.02) were associated with inferior OS; KIT D816V positivity (HR 0.33, 95% CI 0.11 - 0.98, p = 0.04) and midostaurin treatment (HR 0.32, 95% CI 0.08 - 0.72, p = 0.008) were associated with superior OS. These data provide the most comprehensive snapshot of the clinicopathologic, molecular, and treatment landscape of MCL to date, and should help further inform subtyping and prognostication of MCL.
Myelodysplastic syndromes (MDSs) are a heterogeneous group of hematological disorders characterized by ineffective hematopoiesis, enhanced bone marrow apoptosis and frequent progression to acute myeloid leukemia. Several recent studies suggested that, besides the abnormal development of stem cells, microenvironmental alterations are also present in the MDS bone marrow. In this study, we have examined the relative frequencies of stem and progenitor cell subsets of MDS and normal hematopoietic cells growing on stromal cell layers established from MDS patients and from normal donors. When hematopoietic cells from MDS patients were co-cultured with normal stromal cells, the frequency of either early or late cobblestone area-forming cells (CAFC) was significantly lower compared to the corresponding normal control values in 4 out of 8 patients. In the opposite situation, when normal hematopoietic cells were incubated on MDS stromal cells, the CAFC frequencies were decreased in 5 out of 6 patients, compared to normal stromal layer-containing control cultures. Moreover, a soluble Notch ligand (Jagged-1 protein) was an inhibitor of day-35-42 CAFC when normal hematopoietic cells were cultured with normal or MDS stromal cells, but was unable to inhibit MDS stem and early progenitor cell growth (day-35-42 CAFC) on pre-established stromal layers. These findings suggest that in early hematopoietic cells isolated from MDS patients the Notch signal transduction pathway is disrupted. Furthermore, there was a marked reduction in the plasticity of mesenchymal stem cells of MDS patients compared with those of normal marrow donors, in neurogenic and adipogenic differentiation ability and hematopoiesis supporting capacity in vitro. These results are consistent with the hypothesis that when alterations are present in the myelodysplastic stroma environment along with intrinsic changes in a hematopoietic stem/progenitor cell clone, both factors might equally contribute to the abnormal hematopoiesis in MDS.
Compelling biological and epidemiological evidences point to a key role of genetic variants of the TERT and TERC genes in cancer development. We analyzed the genetic variability of these two gene regions using samples of 2,267 multiple myeloma (MM) cases and 2,796 healthy controls. We found that a TERT variant, rs2242652, is associated with reduced MM susceptibility (OR = 0.81; 95% CI: 0.72–0.92; p = 0.001). In addition we measured the leukocyte telomere length (LTL) in a subgroup of 140 cases who were chemotherapy‐free at the time of blood donation and 468 controls, and found that MM patients had longer telomeres compared to controls (OR = 1.19; 95% CI: 0.63–2.24; ptrend = 0.01 comparing the quartile with the longest LTL versus the shortest LTL). Our data suggest the hypothesis of decreased disease risk by genetic variants that reduce the efficiency of the telomerase complex. This reduced efficiency leads to shorter telomere ends, which in turn may also be a marker of decreased MM risk.
Mastocytosis is a unique hematologic neoplasm with complex biology and pathology and a variable clinical course. The disease can essentially be divided into cutaneous mastocytosis (CM) and systemic mastocytosis (SM). In adults, SM is diagnosed in most cases and manifests as either indolent or advanced disease. Patients with advanced SM have an unfavorable prognosis with reduced survival. However, so far, little is known about the prevalence of various categories of SM and about prognostic factors. In an attempt to learn more about the behavior and evolution of various forms of CM and SM, the European Competence Network on Mastocytosis (ECNM) initiated a mastocytosis registry in 2012. In this article, the set up and start phase of this registry are described. Until 2018, more than 3000 patients from 12 countries and 25 centers have been enrolled. In a majority of all patients, robust follow-up data and relevant clinical end points are available. Using this data set, a series of registry projects have been launched, with the aim to validate previously identified diagnostic and prognostic variables and to identify new diseaserelated and patient-related parameters in various forms of mastocytosis. Moreover, the core data set of the registry will be useful to establish multiparametric scoring systems through which prognostication and individualized management of patients with mastocytosis should improve in the foreseeable future. Valent et al.
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