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1.
J Invest Dermatol ; 142(7): 1858-1868.e8, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-34896119

RESUMO

Pigmentation of the human skin is a complex process regulated by many genes. However, only a few have a profound impact on melanogenesis. Transcriptome analysis of pigmented skin compared with analysis of vitiligo skin devoid of melanocytes allowed us to unravel CLEC12B as a melanocytic gene. We showed that CLEC12B, a C-type lectin receptor, is highly expressed in melanocytes and that its expression is decreased in dark skin compared with that in white skin. CLEC12B directly recruits and activates SHP1 and SHP2 through its immunoreceptor tyrosine-based inhibitory motif domain and promotes CRE-binding protein degradation, leading to the downregulation of the downstream MITF pathway. CLEC12B ultimately controls melanin production and pigmentation in vitro and in a model of reconstructed human epidermis. The identification of CLEC12B in melanocytes shows that C-type lectin receptors exert function beyond immunity and inflammation. It also provides insights into the understanding of melanocyte biology and regulation of melanogenesis.


Assuntos
Lectinas Tipo C , Melanócitos , Receptores Mitogênicos , Pigmentação da Pele , Epiderme/metabolismo , Humanos , Lectinas Tipo C/genética , Lectinas Tipo C/metabolismo , Melaninas/metabolismo , Melanócitos/metabolismo , Receptores Mitogênicos/metabolismo , Pele/metabolismo , Pigmentação da Pele/genética
2.
Int J Mol Sci ; 21(1)2019 12 25.
Artigo em Inglês | MEDLINE | ID: mdl-31881723

RESUMO

Myelodysplastic syndrome (MDS) defines a group of heterogeneous hematologic malignancies that often progresses to acute myeloid leukemia (AML). The leading treatment for high-risk MDS patients is azacitidine (Aza, Vidaza®), but a significant proportion of patients are refractory and all patients eventually relapse after an undefined time period. Therefore, new therapies for MDS are urgently needed. We present here evidence that acadesine (Aca, Acadra®), a nucleoside analog exerts potent anti-leukemic effects in both Aza-sensitive (OCI-M2S) and resistant (OCI-M2R) MDS/AML cell lines in vitro. Aca also exerts potent anti-leukemic effect on bone marrow cells from MDS/AML patients ex-vivo. The effect of Aca on MDS/AML cell line proliferation does not rely on apoptosis induction. It is also noteworthy that Aca is efficient to kill MDS cells in a co-culture model with human medullary stromal cell lines, that mimics better the interaction occurring in the bone marrow. These initial findings led us to initiate a phase I/II clinical trial using Acadra® in 12 Aza refractory MDS/AML patients. Despite a very good response in one out 4 patients, we stopped this trial because the highest Aca dose (210 mg/kg) caused serious renal side effects in several patients. In conclusion, the side effects of high Aca doses preclude its use in patients with strong comorbidities.


Assuntos
Aminoimidazol Carboxamida/análogos & derivados , Leucemia Mieloide Aguda/tratamento farmacológico , Síndromes Mielodisplásicas/tratamento farmacológico , Ribonucleosídeos/uso terapêutico , Idoso , Aminoimidazol Carboxamida/farmacologia , Aminoimidazol Carboxamida/uso terapêutico , Apoptose/efeitos dos fármacos , Azacitidina/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios Clínicos como Assunto , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Humanos , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/patologia , Recidiva , Ribonucleosídeos/farmacologia , Falha de Tratamento
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