Sophie Georgin-Lavialle

Mast cell leukemia

Mast cell leukemia (MCL) is a very rare form of aggressive systemic mastocytosis accounting for < 1% of all mastocytosis. It may appear de novo or secondary to previous mastocytosis and shares more clinicopathologic aspects with systemic mastocytosis than with acute myeloid leukemia. Symptoms of mast cell activation-involvement of the liver, spleen, peritoneum, bones, and marrow-are frequent. Diagnosis is based on the presence of ≥ 20% atypical mast cells in the marrow or ≥ 10% in the blood; however, an aleukemic variant is frequently encountered in which the number of circulating mast cells is < 10%. The common phenotypic features of pathologic mast cells encountered in most forms of mastocytosis are unreliable in MCL. Unexpectedly, non-KIT D816V mutations are frequent and therefore, complete gene sequencing is necessary. Therapy usually fails and the median survival time is < 6 months. The role of combination therapies and bone marrow transplantation needs further investigation.

In aggressive forms of mastocytosis, TET2 loss cooperates with c-KITD816V to transform mast cells.

Although a role for oncogenic KIT in driving mast cell disease is clear, the mechanisms driving the multiple phenotypic and clinical manifestations of this disorder are not well elucidated. We now show, using a large cohort of mastocytosis patients, including an almost equal number of aggressive and nonaggressive cases of systemic mastocytosis, that in contrast to the oncogenic KITD816V, TET2 mutation statistically associates with aggressive forms of the disease. By infecting primary murine bone marrow-derived mast cells with KITD816V, we also observe a significant and competitive growth advantage for KITD816V in Tet2-nullizygous compared with wild-type cells. TET2-deficient cells display increased proliferation and can survive in the absence of cytokines. Taken together, these data demonstrate a oncogenic cooperation in mast cells and reveal TET2 mutation as a potential marker to diagnose and predict severe forms of mastocytosis.

Depression in patients with mastocytosis: prevalence, features and effects of masitinib therapy.

Depression in patients with mastocytosis is often reported but its prevalence and characteristics are not precisely described. In addition, the impact of therapies targeting mast cells proliferation, differentiation and degranulation on psychic symptoms of depression have never been investigated. Our objective was to determine the prevalence and to describe features of depression in a large cohort of mastocytosis patients (nu200a=u200a288) and to investigate the therapeutic impact of the protein kinase inhibitor masitinib in depression symptoms. The description of depression was based on the analysis of a database with Hamilton scores using Principal Component Analysis (PCA). Efficacy of masitinib therapy was evaluated using non parametric Wilcoxon test for paired data within a three months period (nu200a=u200a35). Our results show that patients with indolent mastocytosis present an elevated prevalence of depression (64%). Depression was moderate in 56% but severe in 8% of cases. Core symptoms (such as psychic anxiety, depressed mood, work and interests) characterized depression in mastocytosis patients. Masitinib therapy was associated with significant improvement (67% of the cases) of overall depression, with 75% of recovery cases. Global Quality of Life slightly improved after masitinib therapy and did not predicted depression improvement. In conclusion, depression is very frequent in mastocytosis patients and masitinib therapy is associated with the reduction its psychic experiences. We conclude that depression in mastocytosis may originate from processes related to mast cells activation. Masitinib could therefore be a useful treatment for mastocytosis patients with depression and anxiety symptoms.

The telomere/telomerase system in autoimmune and systemic immune-mediated diseases

Telomeres are specialized nucleoproteic structures that cap and protect the ends of chromosomes. They can be elongated by the telomerase enzyme, but in telomerase negative cells, telomeres shorten after each cellular division because of the end replicating problem. This phenomenon leads ultimately to cellular senescence, conferring to the telomeres a role of biological clock. Oxidative stress, inflammation and increased cell renewal are supplementary environmental factors that accelerate age-related telomere shortening. Similar to other types of DNA damage, very short/dysfunctional telomeres activate a DNA response pathway leading to different outcomes: DNA repair, cell senescence or apoptosis. During the last 10 years, studies on the telomere/telomerase system in autoimmune and/or systemic immune-mediated diseases have revealed its involvement in relevant physiopathological processes. Here, we present a literature review of telomere and telomerase homeostasis in systemic inflammatory diseases including systemic lupus erythematosus, rheumatoid arthritis and granulomatous diseases. The available data indicate that both telomerase activity and telomere length are modified in various systemic immune-mediated diseases and appear to be connected with premature immunosenescence. Studies on the telomere/telomerase system open new research avenues for the basic understanding and for therapeutic approaches of these pathologies.

Description of 214 cases of autoimmune congenital heart block: Results of the French neonatal lupus syndrome ☆

BACKGROUNDnCardiac neonatal lupus syndrome is due to anti-SSA or SSB antibodies and mainly includes congenital heart block (CHB) and dilated cardiomyopathy (DCM). Its optimal management is still debated. We report a large series of autoimmune high degree CHB.nnnMETHODSnInclusion criteria in this retrospective study were fetuses or neonates with high-degree CHB associated with maternal anti-SSA/SSB antibodies.nnnRESULTSn214 CHB were included: 202 detected in utero at a median term of 23 weeks gestation (WG) [range 16 to 39 WG] and 12 neonatal cases diagnosed at a median age of 0 days [range birth to 8 days]. The 214 cases of CHB included 202 (94.4%) third-degree CHB, 8 (3.7%) second-degree CHB, and 4 (1.9%) intermittent CHB. In multivariate analysis, the factors associated with feto-neonatal deaths (15.7%) were hydrops (p<0.001; hazard ratio [HR] 12.4 [95% confidence interval (95%CI) 4.7-32.7]) and prematurity (p=0.002; HR 17.1 [95%CI 2.8-103.1]). During a median follow-up of 7 years [birth to 36 years], 148 of 187 children born alive (79.1%) had a pacemaker, 35 (18.8%, one missing data) had DCM, and 22 (11.8%) died. In multivariate analysis, factors associated with child death were in utero DCM (p=0.0157; HR 6.37 [95%CI: 1.25-32.44]), postnatal DCM (p<0.0001; HR 227.58[95%CI: 24.33-2128.46]) and pacemaker implantation (p=0.0035; HR 0.11[95%CI: 0.02-0.51]). The use of fluorinated steroids was neither associated with survival nor with regression of 2nd degree CHB.nnnCONCLUSIONnIn this second largest series of CHB, we confirm some of the previous results. We were unable to find data supporting the routine use of in utero fluorinated steroids.

Evidence for cognitive impairment in mastocytosis: prevalence, features and correlations to depression.

Mastocytosis is a heterogeneous disease characterized by mast cells accumulation in one or more organs. We have reported that depression is frequent in mastocytosis, but although it was already described, little is known about the prevalence and features of cognitive impairment. Our objective was to describe the prevalence and features of cognitive impairment in a large cohort of patients with this rare disease (nu200a=u200a57; mean ageu200a=u200a45) and to explore the relations between memory impairment and depression. Objective memory impairment was evaluated using the 3rd edition of the Clinical Memory scale of Wechsler. Depression symptoms were evaluated using the Hamilton Depression Rating Scale. Age and education levels were controlled for all patients. Patients with mastocytosis presented high levels of cognitive impairment (memory and/or attention) (nu200a=u200a22; 38.6%). Cognitive impairment was moderate in 59% of the cases, concerned immediate auditory (41%) and working memory (73%) and was not associated to depression (p≥0.717). In conclusion, immediate auditory memory and attention impairment in mastocytosis are frequent, even in young individuals, and are not consecutive to depression. In mastocytosis, cognitive complaints call for complex neuropsychological assessment. Mild-moderate cognitive impairment and depression constitute two specific but somewhat independent syndromes in mastocytosis. These results suggest differential effects of mast-cell activity in the brain, on systems involved in emotionality and in cognition.

Mast cell leukemia: identification of a new c-Kit mutation, dup(501-502), and response to masitinib, a c-Kit tyrosine kinase inhibitor.

Objective:u2002 Most patients with systemic mastocytosis bear mutations in the tyrosine kinase receptor gene c‐Kit. Limited treatment options exist for mast cell leukemia, a rare form of systemic mastocytosis associated with a dire prognosis. Our aim was to investigate c‐Kit mutations associated with mast cell leukemia and find new treatment for this severe form of mastocytosis.

Blood CD34−c-Kit+ cell rate correlates with aggressive forms of systemic mastocytosis and behaves like a mast cell precursor

Mastocytosis is a heterogeneous disease characterized by the accumulation of mast cells in one or more organs. Our objective was to identify a peripheral mast cell precursor and assess its variation rate in mastocytosis. A peripheral blood phenotypic analysis was performed among 50 patients with mastocytosis who were enrolled in a prospective multicentric French study, and the phenotypic analysis results of the patients were compared with those of healthy donors. The rate of peripheral blood CD34(-)c-Kit(+) cells correlated with the severity of mastocytosis. This cellular population was isolated from healthy donors as well as from patients with systemic mastocytosis. After 30 days of culture, the CD34(-)c-Kit(+) cells gave birth to mature mast cells, indicating that this cellular population constitutes a mast cell circulating precursor. Monitoring peripheral CD34(-)c-Kit(+) cells by flow cytometry could be a useful and low-invasive tool to determine the disease severity and the relapses and to assess treatment efficiency.

Actualités sur la compréhension et le traitement des mastocytoses systémiques

PURPOSEnMast cell disorders are defined by an abnormal accumulation of tissue mast cells in one or more organ systems. Clinical symptoms in mastocytosis result from mast cells derived mediators and, less frequently, from destructive infiltration of mast cells. Systemic mastocytosis is regressive among children, whereas the disease is persistent among adults. A clonal haematological non-mast cell lineage disease can be associated. The clinical course in these patients is variable ranging from asymptomatic for years to highly aggressive and rapidly devastating. Until recently, the only treatment of this incurable disease was symptomatic.nnnCURRENT KNOWLEDGE AND KEY POINTSnRecent advances were done in understanding the physiopathology of this myeloproliferative syndrome which results from an activating mutation of the stem cell factor receptor: C-Kit. A somatic C-Kit mutation is usually detectable in mast cells and their progenitors. Different mutations were found and the mutation D816V is the most frequent. Their specific transduction paths were also studied. Diagnosis of systemic mastocytosis does not only rest upon pathological examination but also on molecular as well as immunological and immunochemical tools.nnnFUTURE PROSPECTS AND PROJECTSnPhysiopathological advancements led to suggest new treatments in order to directly inhibit proliferative paths of masts cells such as tyrosine kinase inhibitors and rapamycin.

Leukocyte telomere length in mastocytosis: Correlations with depression and perceived stress

BACKGROUNDnMastocytosisis a rare disease associated with chronic symptoms related to mast cell mediator release. Patients with mastocytosis display high level of negative emotionality such as depression and stress sensibility. Brain mast cells are mainly localized in the diencephalon, which is linked to emotion regulatory systems. Negative emotionality has been shown to be associated with telomere shortening. Taken together these observations led us to hypothesize that mast cells activity could be involved in both negative emotionality and telomere shortening in mastocytosis.nnnOBJECTIVEnTo demonstrate a possible relationship between negative emotionality in mastocytosis and leukocytes telomere length.nnnMETHODSnLeukocyte telomere length and telomerase activity were measured among mastocytosis patients and were correlated with perceived stress and depression assessed by the Beck Depression Inventory revised and the Perceived Stress Scale.nnnRESULTSnMild-severe depression scores were frequent (78.9%) as well as high perceived stress (42.11%). Telomere length was correlated to perceived stress (r=0.77; p=0.0001) but not to depression in our population. Patients displaying Wild-type KIT significantly presented higher perceived stress levels. Patients with the D816VC KIT mutation who had high perceived stress scores displayed significantly shorter telomere but not if they had high depression scores.nnnCONCLUSIONnThese findings suggest that high perceived stress in mastocytosis could accelerate the rate of leukocytes telomere shortening. Since mastocytosis is, by definition, a mast cell mediated disease; these cells could be involved in this phenomenon. Mechanistic causal relationships between these parameters need to be investigated.