The natural history of Gaucher disease type 1 in 31 patients over a median of 15 years: a retrospective study.

BACKGROUND AND AIMS: The natural history of untreated patients with type 1 Gaucher disease (GD1) is not well documented, and there is controversy over when and how to treat such patients, especially if they are only mildly symptomatic. Treatment of GD1 is inconvenient, very costly, and may result in undesirable side effects. We documented the clinical history of 31 untreated patients with GD1 followed in our clinic for 4-26 (median 15) years. METHODS: This was a retrospective, observational study of the progress of untreated adult patients with GD1 followed by blood tests (haemoglobin, platelet counts, ferritin and chitotriosidase), organ volumes (spleen and liver), bone manifestations (through magnetic resonance imaging and dual X-ray absorptiometry scans) and neurological and quality of life issues. Statistical analyses were performed with the use of the Student paired t test and the modified Wald test for 95% confidence intervals. RESULTS: We found that the above parameters remained stable in most patients over a period of 4-26 (median 15) years. Five patients progressed from normal bone density to osteopenia and two from osteopenia to osteofibrosis; six were peri- or post-menopausal females. The DS-3 was stable over time. Only four of the 31 patients were started on enzyme or substrate reduction therapy. CONCLUSIONS: Our results demonstrate that many patients with GD1, provided with close follow-up by a specialist centre, can be followed for many years without requiring treatment and with no or minimal worsening of their GD1 manifestations.

Enzyme replacement therapy with taliglucerase alfa: 36-month safety and efficacy results in adult patients with Gaucher disease previously treated with imiglucerase.

Taliglucerase alfa is the first available plant cell-expressed human recombinant therapeutic protein. It is indicated for treatment of patients with type 1 Gaucher disease (GD) in adult and pediatric patients in several countries. Study PB-06-002 examined the safety and efficacy of taliglucerase alfa for 9 months in patients who previously received imiglucerase. The results of adult patients from Study PB-06-002 who continued receiving taliglucerase alfa in extension Study PB-06-003 for up to 36 months are reported here. Eighteen patients received at least one dose of taliglucerase alfa in Study PB-06-003; 10 patients completed 36 total months of therapy, and four patients who transitioned to commercial drug completed 30-33 months of treatment. In patients who completed 36 total months of treatment, mean percent (±standard error) changes from baseline/time of switch to taliglucerase alfa to 36 months were as follows: hemoglobin concentration, -1.0% (±1.9%; n = 10); platelet count, +9.3% (±9.8%; n = 10); spleen volume measured in multiples of normal (MN), -19.8% (±9.9%; n = 7); liver volume measured in MN, +0.9% (±5.4%; n = 8); chitotriosidase activity, -51.5% (±8.1%; n = 10); and CCL18 concentration, -36.5 (±8.0%; n = 10). Four patients developed antidrug antibodies, including one with evidence of neutralizing activity in vitro. All treatment-related adverse events were mild or moderate and transient. The 36-month results of switching from imiglucerase to taliglucerase alfa treatment in adults with GD provide further data on the clinical safety and efficacy of taliglucerase alfa beyond the initial 9 months of the original study. www.clinicaltrials.gov identifier NCT00705939. Am. J. Hematol. 91:661-665, 2016. © 2016 Wiley Periodicals, Inc.

Long-term efficacy and safety results of taliglucerase alfa up to 36 months in adult treatment-naïve patients with Gaucher disease.

Taliglucerase alfa is an intravenous enzyme replacement therapy approved for treatment of type 1 Gaucher disease (GD), and is the first available plant cell-expressed recombinant therapeutic protein. Herein, we report long-term safety and efficacy results of taliglucerase alfa in treatment-naïve adult patients with GD. Patients were randomized to receive taliglucerase alfa 30 or 60 U/kg every other week, and 23 patients completed 36 months of treatment. Taliglucerase alfa (30 U/kg; 60 U/kg, respectively) resulted in mean decreases in spleen volume (50.1%; 64.6%) and liver volume (25.6%; 24.4%) with mean increases in hemoglobin concentration (16.0%; 35.8%) and platelet count (45.7%; 114.0%), and mean decreases in chitotriosidase activity (71.5%; 82.2%). All treatment-related adverse events were mild to moderate in intensity and transient. The most common adverse events were nasopharyngitis, arthralgia, upper respiratory tract infection, headache, pain in extremity, and hypertension. These 36-month results of taliglucerase alfa in treatment-naïve adult patients with GD demonstrate continued improvement in disease parameters with no new safety concerns. These findings extend the taliglucerase alfa clinical safety and efficacy dataset. www.clinicaltrials.gov identifier NCT00705939. Am. J. Hematol. 91:656-660, 2016. © 2016 Wiley Periodicals, Inc.

Effect of oral eliglustat on splenomegaly in patients with Gaucher disease type 1: the ENGAGE randomized clinical trial.

IMPORTANCE: Gaucher disease type 1 is characterized by hepatosplenomegaly, anemia, thrombocytopenia, and skeletal disease. A safe, effective oral therapy is needed. OBJECTIVE: To determine whether eliglustat, a novel oral substrate reduction therapy, safely reverses clinical manifestations in untreated adults with Gaucher disease type 1. DESIGN, SETTING, AND PARTICIPANTS: Phase 3, randomized, double-blind, placebo-controlled trial conducted at 18 sites in 12 countries from November 2009 to July 2012 among eligible patients with splenomegaly plus thrombocytopenia and/or anemia. Of 72 patients screened, 40 were enrolled. INTERVENTIONS: Patients were stratified by spleen volume and randomized 1:1 to receive eliglustat (50 or 100 mg twice daily; n = 20) or placebo (n = 20) for 9 months. MAIN OUTCOMES AND MEASURES: The primary efficacy end point was percentage change in spleen volume in multiples of normal from baseline to 9 months; secondary efficacy end points were change in hemoglobin level and percentage changes in liver volume and platelet count. RESULTS: All patients had baseline splenomegaly and thrombocytopenia (mostly moderate or severe), most had mild or moderate hepatomegaly, and 20% had mild anemia. Least-square mean spleen volume decreased by 27.77% (95% CI, -32.57% to -22.97%) in the eliglustat group (from 13.89 to 10.17 multiples of normal) vs an increase of 2.26% (95% CI, -2.54% to 7.06%) in the placebo group (from 12.50 to 12.84 multiples of normal) for an absolute treatment difference of -30.03% (95% CI, -36.82% to -23.24%; P < .001). For the secondary end points, the least-square mean absolute differences between groups all favored eliglustat, with a 1.22-g/dL increase in hemoglobin level (95% CI, 0.57-1.88 g/dL; P < .001), 6.64% decrease in liver volume (95% CI, -11.37% to -1.91%; P = .007), and 41.06% increase in platelet count (95% CI, 23.95%-58.17%; P < .001). No serious adverse events occurred. One patient in the eliglustat group withdrew (non-treatment related); 39 of the 40 patients transitioned to an open-label extension study. CONCLUSIONS AND RELEVANCE: Among previously untreated adults with Gaucher disease type 1, treatment with eliglustat compared with placebo for 9 months resulted in significant improvements in spleen volume, hemoglobin level, liver volume, and platelet count. The clinical significance of these findings is uncertain, and more definitive conclusions about clinical efficacy and utility will require comparison with the standard treatment of enzyme replacement therapy as well as longer-term follow-up. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00891202.

A Phase 3, multicenter, open-label, switchover trial to assess the safety and efficacy of taliglucerase alfa, a plant cell-expressed recombinant human glucocerebrosidase, in adult and pediatric patients with Gaucher disease previously treated with imiglucerase.

Taliglucerase alfa is a ß-glucosidase enzyme replacement therapy (ERT) approved in the US and other countries for the treatment of Gaucher disease (GD) in adults and is approved in pediatric and adult patients in Australia and Canada. It is the first approved plant cell-expressed recombinant human protein. A Phase 3, multicenter, open-label, 9-month study assessed safety and efficacy of switching to taliglucerase alfa in adult and pediatric patients with GD treated with imiglucerase for at least the previous 2years. Patients with stable disease were offered taliglucerase alfa treatment using the same dose (9-60U/kg body weight) and regimen of administration (every 2weeks) as imiglucerase. This report summarizes results from 26 adult and 5 pediatric patients who participated in the trial. Disease parameters (spleen and liver volumes, hemoglobin concentration, platelet count, and biomarker levels) remained stable through 9months of treatment in adults and children following the switch from imiglucerase. All treatment-related adverse events were mild or moderate in severity and transient in nature. Exploratory parameters of linear growth and development showed positive outcomes in pediatric patients. These findings provide evidence of the efficacy and safety profile of taliglucerase alfa as an ERT for GD in patients previously treated with imiglucerase. This trial was registered at www.clinicaltrials.gov as # NCT00712348.

Pivotal trial with plant cell-expressed recombinant glucocerebrosidase, taliglucerase alfa, a novel enzyme replacement therapy for Gaucher disease.

Taliglucerase alfa (Protalix Biotherapeutics, Carmiel, Israel) is a novel plant cell-derived recombinant human ß-glucocerebrosidase for Gaucher disease. A phase 3, double-blind, randomized, parallel-group, comparison-dose (30 vs 60 U/kg body weight/infusion) multinational clinical trial was undertaken. Institutional review board approvals were received. A 9-month, 20-infusion trial used inclusion/exclusion criteria in treatment-naive adult patients with splenomegaly and thrombocytopenia. Safety end points were drug-related adverse events: Ab formation and hypersensitivity reactions. Primary efficacy end point was reduction in splenic volume measured by magnetic resonance imaging. Secondary end points were: changes in hemoglobin, hepatic volume, and platelet counts. Exploratory parameters included biomarkers and bone imaging. Twenty-nine patients (11 centers) completed the protocol. There were no serious adverse events; drug-related adverse events were mild/moderate and transient. Two patients (6%) developed non-neutralizing IgG Abs; 2 other patients (6%) developed hypersensitivity reactions. Statistically significant spleen reduction was achieved at 9 months: 26.9% (95% confidence interval [CI]: -31.9, -21.8) in the 30-unit dose group and 38.0% (95% CI: -43.4, -32.8) in the 60-unit dose group (both P < .0001); and in all secondary efficacy end point measures, except platelet counts at the lower dose. These results support safety and efficacy of taliglucerase alfa for Gaucher disease.

Hermansky-Pudlak syndrome type 7 (HPS-7) results from mutant dysbindin, a member of the biogenesis of lysosome-related organelles complex 1 (BLOC-1).

Hermansky-Pudlak syndrome (HPS; MIM 203300) is a genetically heterogeneous disorder characterized by oculocutaneous albinism, prolonged bleeding and pulmonary fibrosis due to abnormal vesicle trafficking to lysosomes and related organelles, such as melanosomes and platelet dense granules. In mice, at least 16 loci are associated with HPS, including sandy (sdy; ref. 7). Here we show that the sdy mutant mouse expresses no dysbindin protein owing to a deletion in the gene Dtnbp1 (encoding dysbindin) and that mutation of the human ortholog DTNBP1 causes a novel form of HPS called HPS-7. Dysbindin is a ubiquitously expressed protein that binds to alpha- and beta-dystrobrevins, components of the dystrophin-associated protein complex (DPC) in both muscle and nonmuscle cells. We also show that dysbindin is a component of the biogenesis of lysosome-related organelles complex 1 (BLOC-1; refs. 9-11), which regulates trafficking to lysosome-related organelles and includes the proteins pallidin, muted and cappuccino, which are associated with HPS in mice. These findings show that BLOC-1 is important in producing the HPS phenotype in humans, indicate that dysbindin has a role in the biogenesis of lysosome-related organelles and identify unexpected interactions between components of DPC and BLOC-1.

Occurrence of Amyotrophic Lateral Sclerosis in Type 1 Gaucher Disease.

OBJECTIVE: To report the association between type 1 Gaucher disease (GD1) and amyotrophic lateral sclerosis (ALS) in 3 unrelated families and to explore whether GBA variants influence the risk of ALS. METHODS: We conducted retrospective chart reviews of patients with GD1 or their family members diagnosed with ALS. To further investigate whether there is an association between ALS and GD, we performed exploratory analyses for the presence of GBA variants in 3 ALS cohorts from Toronto (Canada), Montreal (Canada), and Project MinE (international), totaling 4,653 patients with ALS and 1,832 controls. RESULTS: We describe 2 patients with GD1 and 1 obligate GBA mutation carrier (mother of GD1 patient) with ALS. We identified 0 and 8 GBA carriers in the Toronto and Montreal cohorts, respectively. The frequencies of GBA variants in patients with ALS in the Montreal and Project MinE cohorts were similar to those of Project MinE controls or Genome Aggregation Database population controls. CONCLUSIONS: The occurrence of ALS in biallelic or monoallelic GBA mutation carriers described here, in addition to common pathogenic pathways shared by GD1 and ALS, suggests that GBA variants could influence ALS risk. However, analyses of GBA variants in ALS cohorts did not reveal a meaningful association. Examination of larger cohorts and neuropathologic studies will be required to elucidate whether patients with GD1 are indeed at increased risk for ALS.

Gaucher disease: a systematic review and meta-analysis of bone complications and their response to treatment.

Type 1 Gaucher disease (GD1) is an inherited lysosomal storage disease, which is often managed by enzyme replacement therapy (ERT). The bone response to ERT is usually slower than visceral and hematological responses. There is uncertainty as to whether an increase in the dosage of ERT has a beneficial effect. The aim of our study was to determine whether or not there is sufficient evidence to make a definitive statement about the effects of ERT and substrate reduction therapy (SRT) on bone marrow infiltration and bone mineral density (BMD) in GD1. We conducted a systematic review of all studies examining the effects of ERT and SRT on bony complications of GD1 published before July 2008. The studies were identified by a computerized search with use of Medline, Embase, The Cochrane Database of Systematic Reviews, The Cochrane Central Register of Controlled Trials (CCTR), and bibliographies of papers subsequently retrieved from the search. Three hundred studies were grouped according to whether they deal with the natural history of GD1 or therapeutic issues, and 17 studies were included in the review. The results from our systematic review suggest that further investigations, such as better analysis of the Gaucher Registry, are needed on the effects of ERT and SRT on bony complications of GD1. Studies on the effects of the newly identified velaglucerase and the plant-derived glucocerebrosidase on bony complications of GD1 are also needed.

Parkinsonism in Patients with Neuronopathic (Type 3) Gaucher Disease: A Case Series.

BACKGROUND: The link between Parkinson's disease (PD), the second most common neurodegenerative disorder, and nonneuronopathic Gaucher disease (GD) is well established. Currently, PD is primarily associated with nonneuronopathic GD; however, with currently available treatments, patients with chronic neuronopathic GD, who historically had a shortened life span, are now living well into their 50s and beyond. CASES: We highlight 4 patients with chronic neuronopathic GD with parkinsonian features, describing their GD genotype and phenotype as well as the presentation and progression of their parkinsonism. Symptoms presented in their fourth or fifth decade of life, and include unilateral bradykinesia and/or tremor. Of the patients, 3 had cognitive impairment. The fourth patient has not shown cognitive decline 6 years after PD onset. CONCLUSION: This small series highlights that PD is not exclusively associated with nonneuronopathic GD and that as the chronic neuronopathic GD population ages, the clinical spectrum and heterogeneity of neurological manifestations may include parkinsonism.

The clinical course of untreated Gaucher disease in 22 patients over 10 years: hematological and skeletal manifestations.

Gaucher disease (GD) is a lysosomal storage disorder characterized by anemia and thrombocytopenia, hepatosplenomegaly, and skeletal involvement. The management of Gaucher disease was improved by the development of enzyme replacement therapy (ERT). However, the bone response to ERT is generally slower compared to other clinical manifestations. Some have recommended the early use of ERT to prevent the development of severe skeletal complications. Because we have access to over 30 untreated patients in Ontario, we questioned the extent to which complications progress in severity over a long period of time. We examined retrospectively the natural history of GD and the extent of skeletal manifestations in 22 untreated type 1 GD adult patients (mean age, 49+/-3.3; range, 20-81 years). The patients were followed for a median of 9.5 years (range, 3-16 years). Hemoglobin (Hb) concentration did not significantly change over time (mean baseline concentration of 12.8+/-0.27 g/dL vs. mean recent concentration of 12.6+/-0.37 g/dL, p=0.65). Mean platelet count also remained relatively stable over time (mean baseline count of 138+/-13x10(9)/L vs. mean recent count of 138.5+/-18x10(9)/L, p=0.98). Mean ferritin and ACE concentrations were elevated and were stable over time. Liver volumes decreased over time (mean baseline liver volume of 1.2xnormal (N) vs. mean recent volume of 1.06xN, p=0.27) and 6 of 22 (27%) patients had moderate hepatomegaly (liver volume, 1.25-2.5xN). Spleen volumes remained stable over time (mean baseline spleen volume of 6.6xN vs. mean recent volume of 5.2xN, p=0.5). None of the changes was statistically significant. Four of 20 (20%) patients had moderate splenomegaly (spleen volume, 5-15xN), 2 of 20 (10%) had marked splenomegaly (spleen volume, >or=15xN), and 2 of 22 (9%) had had splenectomy. The most common skeletal manifestations were infiltration of the bone marrow in 16 of 22 (73%) patients followed by osteopenia in 15 of 22 (68%), Erlenmeyer flask deformity in 13 of 22 (59%), and infarctions in 6 of 22 (27%) patients. We observed that bone disease remained relatively stable over time in most patients, although three patients developed new infarcts over time, one developed an avascular necrosis (AVN), and four had an increase in the degree of osteopenia. Although GD and its skeletal complications progress in severity in some patients, our results suggest that GD complications, including bony disease, may stabilize over time. Therefore, early use of ERT may not be necessary in all type 1 GD patients.

The female Gaucher patient: the impact of enzyme replacement therapy around key reproductive events (menstruation, pregnancy and menopause).

BACKGROUND: The principal manifestations of type 1 Gaucher disease (GD) (increased risk of bleeding, anaemia, splenomegaly, hepatomegaly and bone disease) are likely to affect females during reproductive events such as menarche and menstruation; fertility, pregnancy, parity, delivery and lactation; and menopause. In order to determine the optimal management of female Gaucher patients based on available data, we examine reproductive events and GD in untreated and alglucerase and/or imiglucerase-treated females. METHODS: A panel of international clinicians experienced in the management of GD reviewed and presented evidence from peer-reviewed literature, a pharmacovigilance database on imiglucerase, and their own clinical experience to support discussions and recommendations. Nine panel members completed a 130-item-questionnaire on the outcomes of the management of female patients in their clinical practice. Results, covering menarche (137 females), menstruation (261 reports), fertility (295 females), pregnancy (416 pregnancies in 247 women) and menopause (45 women) were analysed. Data from a recent Canadian survey on 50 patients with 39 pregnancies, the imiglucerase pharmacovigilance database (100 pregnancies), and relevant literature (56 items covering 398 pregnancies in 205 women) were also reviewed. KEY RESULTS: Menarche: May be delayed in girls with GD. Menorrhagia: Appears to be more common in GD than in the non-Gaucher population and may be ameliorated by alglucerase and/or imiglucerase treatment (menorrhagia in 67/133 (50.4%) untreated females compared with 37/128 (28.9%) treated; Mann-Whitney U test: p=0.001). Fertility: There is no evidence of decreased fertility in GD. Pregnancy: Pregnancy in GD may be complicated by haematological disease, organomegaly and bone involvement. GD diagnosis occurs frequently during pregnancy. Questionnaire results demonstrate: a reduced risk of spontaneous abortion in women treated with alglucerase and/or imiglucerase (untreated: 26/189 (13.8%); treated 1/58 (1.7%) chi(2)p=0.010); reduced risk of Gaucher-related complications during delivery (untreated 43/109 (39.4%); treated 3/46 (6.5%) chi(2)p<0.0005): and a reduced risk of Gaucher-related complications during the post partum period (untreated 15/71 (21.1%); treated 3/43 (7%) chi(2)p=0.014). There is no evidence to date of any untoward effect of alglucerase and/or imiglucerase on the fetus, or on infants breast fed by mothers receiving alglucerase and/or imiglucerase. Menopause: The impact of GD on menopause requires further study especially in relation to bone pathology. CONCLUSIONS: On the basis of this review, GD may have an impact on reproductive events in affected women. Enzyme therapy may have benefits in reducing menorrhagia, spontaneous abortions and complications associated with delivery and the postpartum period.

Three cases of multi-generational Gaucher disease and colon cancer from an Ashkenazi Jewish family: A lesson for cascade screening.

Gaucher disease (GD) is one of the commonest lysosomal storage diseases that is inherited in an autosomal recessive manner and affects 1 in 50,000 to 100,000 people in the general population. The frequency is much higher (1 in 500 to 1000) in people of Ashkenazi Jewish heritage due to a founder effect. GD is caused by decreased or absent activity of ß-glucosidase with subsequent accumulation of the substrate glucosylceramide in macrophages due to genetic alterations in the GBA gene. These often accumulate in the spleen, liver and bone marrow. Three types exist, with type 1 being the most common, also referred to as non-neuronopathic GD. A broad clinical spectrum exists; patients of any age may manifest with hepatosplenomegaly, anaemia, thrombocytopenia, lung disease, bone abnormalities or may remain asymptomatic throughout their lifespan. Multi-generational disease does not usually occur because the risk of disease with each pregnancy, presuming both parents are carriers of the condition, is 25%. Herein, we report an Ashkenazi Jewish family with multi-generational GD type 1 and multigenerational colon cancer in the same three individuals, and reinforce the importance of cascade screening in families with genetic conditions.

Combined miglustat and enzyme replacement therapy in two patients with type 1 Gaucher disease: two case reports.

BACKGROUND: Intravenous enzyme replacement therapy is a first-line therapy for Gaucher disease type 1, and substrate reduction therapy represents an oral treatment alternative. Both enzyme replacement therapy and substrate reduction therapy are generally used as monotherapies in Gaucher disease. However, one randomized study and several case reports have described combination therapy over short time periods. CASE PRESENTATION: We report two female Gaucher disease type 1 patients of mainly Anglo-Saxon descent, where combined enzyme replacement therapy and miglustat substrate reduction therapy were administered to overcome refractory clinical symptoms. The first patient was diagnosed at age 17 and developed Gaucher disease-related bone manifestations that worsened despite starting imiglucerase enzyme replacement therapy. After switching to miglustat substrate reduction therapy, her bone symptoms improved, but she developed tremors and eventually switched back to enzyme replacement therapy. Miglustat was later recommenced in combination with ongoing enzyme replacement therapy due to continued bone pain, and her bone symptoms improved along with maintained visceral manifestations. Enzyme replacement therapy was subsequently tapered off and the patient has since been successfully maintained on miglustat. The second patient was diagnosed aged 3, and commenced imiglucerase enzyme replacement therapy aged 15. After 9 years on enzyme replacement therapy she switched to miglustat substrate reduction therapy and her core symptoms were maintained/stable for 3 years. Imiglucerase enzyme replacement therapy was later added as a boost to therapy and her symptoms were subsequently maintained over a 2.3-year period. However, miglustat was discontinued due to her relocation, necessitating an increase in enzyme replacement therapy dose. Overall, both patients benefited from combination therapy. CONCLUSION: While the majority of Gaucher disease type 1 patients will not need treatment with both substrate reduction therapy and enzyme replacement therapy, the current case reports demonstrate that judicious use of combination therapy may be of benefit in some cases.

Cytogenetic aberrations and immunoglobulin VH gene mutations in clinically benign CD5- monoclonal B-cell lymphocytosis.

The finding of monoclonal B-cell lymphocytosis (MBL) raises questions on the nature of clonal cell expansion and its risk of progression. We identified and characterized 7 cases of clinically benign clonal B-cell lymphocytosis. The clonal lymphocytes were clearly of CD5- and non-chronic lymphocytic leukemia (CLL) phenotype. All cases had mild to moderate absolute lymphocytosis. The clonal population accounted for 95% to 99% of B cells. For a follow-up period of 4 to 16 years, clonal lymphocytosis was persistent but virtually not progressing. Patients' conditions remained clinically stable and asymptomatic. The clonal populations had somatic hypermutations of the VH gene in 6 cases, indicating a germinal center or post-germinal center B-lymphocyte origin. Clonal cytogenetic aberrations were found in 5 of 6 cases, with 2 clones bearing isochromosome 17q that resulted in loss of p53 and 2 other clones with 7q abnormalities. By the presence of absolute lymphocytosis, this series differs from MBL cases identified by sensitive flow cytometry in normal populations. The phenotypic profiles are distinct from that of benign CLL. We suggest these CD5-B-cell lymphocytosis cases may represent an intermediate condition between covert clonal expansions and overt malignancy.

Overexpression of SOCS-2 and SOCS-3 genes reverses erythroid overgrowth and IGF-I hypersensitivity of primary polycythemia vera (PV) cells.

Polycythemia vera (PV), an acquired, chronic, clonal disorder arising in a multipotential hematopoietic progenitor cell, is characterized by hyperplasia of three major myeloid lineages, with a pronounced increase in cells of the erythroid lineage. Erythroid progenitor cells in PV are strikingly hypersensitive to insulin-like growth factor-I (IGF-I); this effect is specific and is mediated through the IGF-I receptor. To investigate the possibility that in PV the increase in number of erythroid progenitors and their hypersensitivity to IGF-I result from a defect in negative regulation of cytokine activity, we examined the expression of members of the SOCS gene family. Circulating mononuclear cells, grown in serum-free methylcellulose medium in the presence of IGF-I, produced BFU-E-derived colonies whose cells revealed a reduction of SOCS-2 and SOCS-3 expression in PV only. Overexpression of these genes in transfected PV cells reduced their erythroid overgrowth and IGF-I hypersensitivity. We hypothesize that a defect in expression of SOCS-2 and SOCS-3 genes may be crucial for the IGF-I hypersensitivity and progressive increase in erythroid cell population size characteristic of PV.