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1.
Blood Adv ; 8(5): 1234-1249, 2024 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-38207211

RESUMO

ABSTRACT: JAK 2-V617F is the most frequent somatic mutation causing myeloproliferative neoplasm (MPN). JAK2-V617F can be found in healthy individuals with clonal hematopoiesis of indeterminate potential (CHIP) with a frequency much higher than the prevalence of MPNs. The factors controlling the conversion of JAK2-V617F CHIP to MPN are largely unknown. We hypothesized that interleukin-1ß (IL-1ß)-mediated inflammation can favor this progression. We established an experimental system using bone marrow (BM) transplantations from JAK2-V617F and GFP transgenic (VF;GFP) mice that were further crossed with IL-1ß-/- or IL-1R1-/- mice. To study the role of IL-1ß and its receptor on monoclonal evolution of MPN, we performed competitive BM transplantations at high dilutions with only 1 to 3 hematopoietic stem cells (HSCs) per recipient. Loss of IL-1ß in JAK2-mutant HSCs reduced engraftment, restricted clonal expansion, lowered the total numbers of functional HSCs, and decreased the rate of conversion to MPN. Loss of IL-1R1 in the recipients also lowered the conversion to MPN but did not reduce the frequency of engraftment of JAK2-mutant HSCs. Wild-type (WT) recipients transplanted with VF;GFP BM that developed MPNs had elevated IL-1ß levels and reduced frequencies of mesenchymal stromal cells (MSCs). Interestingly, frequencies of MSCs were also reduced in recipients that did not develop MPNs, had only marginally elevated IL-1ß levels, and displayed low GFP-chimerism resembling CHIP. Anti-IL-1ß antibody preserved high frequencies of MSCs in VF;GFP recipients and reduced the rate of engraftment and the conversion to MPN. Our results identify IL-1ß as a potential therapeutic target for preventing the transition from JAK2-V617F CHIP to MPNs.


Assuntos
Transtornos Mieloproliferativos , Animais , Camundongos , Animais Geneticamente Modificados , Transplante de Medula Óssea , Células-Tronco Hematopoéticas , Interleucina-1beta , Transtornos Mieloproliferativos/genética
2.
Nat Commun ; 13(1): 5346, 2022 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-36100613

RESUMO

Interleukin-1ß (IL-1ß) is a master regulator of inflammation. Increased activity of IL-1ß has been implicated in various pathological conditions including myeloproliferative neoplasms (MPNs). Here we show that IL-1ß serum levels and expression of IL-1 receptors on hematopoietic progenitors and stem cells correlate with JAK2-V617F mutant allele fraction in peripheral blood of patients with MPN. We show that the source of IL-1ß overproduction in a mouse model of MPN are JAK2-V617F expressing hematopoietic cells. Knockout of IL-1ß in hematopoietic cells of JAK2-V617F mice reduces inflammatory cytokines, prevents damage to nestin-positive niche cells and reduces megakaryopoiesis, resulting in decrease of myelofibrosis and osteosclerosis. Inhibition of IL-1ß in JAK2-V617F mutant mice by anti-IL-1ß antibody also reduces myelofibrosis and osteosclerosis and shows additive effects with ruxolitinib. These results suggest that inhibition of IL-1ß with anti-IL-1ß antibody alone or in combination with ruxolitinib could have beneficial effects on the clinical course in patients with myelofibrosis.


Assuntos
Interleucina-1beta/metabolismo , Janus Quinase 2/genética , Transtornos Mieloproliferativos , Neoplasias , Osteosclerose , Mielofibrose Primária , Animais , Janus Quinase 2/metabolismo , Camundongos , Camundongos Knockout , Transtornos Mieloproliferativos/tratamento farmacológico , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/metabolismo , Nitrilas , Osteosclerose/genética , Mielofibrose Primária/tratamento farmacológico , Mielofibrose Primária/genética , Pirazóis , Pirimidinas
3.
J Child Sex Abus ; 28(8): 990-1006, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31225780

RESUMO

Personality traits are considered as an important aspect in the assessment of child sex offenders (CSOs). The current study sought to elucidate the association between neuroticism, psychopathy, and abusive behavior in low risk CSOs. 43 pedophilic CSOs and 21 controls (CTLs) completed the NEO-Personality Inventory-Revised (NEO-PI-R), Psychopathy Checklist: Screening Version (PCL:SV), and Multiphasic Sex Inventory (MSI). Our results revealed small differences in PCL scores between CSOs and CTLs, with comparatively low levels of psychopathy in both groups. Higher levels of neuroticism were associated with higher PCL scores, in both CSOs and CTLs. However, higher PCL scores in CSOs did not correlate with higher MSI total scores on the subscale child molest. These findings suggest an ambiguous role of psychopathy in CSOs: higher levels of psychopathy co-occur with higher levels of neuroticism, but psychopathy does apparently not modulate abusive behavior, at least not in low risk offenders, as currently investigated.


Assuntos
Transtorno da Personalidade Antissocial/psicologia , Abuso Sexual na Infância/psicologia , Neuroticismo , Personalidade , Adulto , Estudos de Casos e Controles , Criança , Psiquiatria Legal , Humanos , Masculino , Inventário de Personalidade/normas
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