RESUMO
Heat shock protein 27 (HSP27/HSPB1) is a stress-inducible chaperone that facilitates cancer development by its proliferative and anti-apoptotic functions. The OGX-427 antisense oligonucleotide against HSP27 has been reported to be beneficial against idiopathic pulmonary fibrosis. Here we show that OGX-427 is effective in two murine models of thrombopoietin- and JAKV617F-induced myelofibrosis. OGX-427 limits disease progression and is associated with a reduction in spleen weight, in megakaryocyte expansion and, for the JAKV617F model, in fibrosis. HSP27 regulates the proliferation of JAK2V617F-positive cells and interacts directly with JAK2/STAT5. We also show that its expression is increased in both CD34+ circulating progenitors and in the serum of patients with JAK2-dependent myeloproliferative neoplasms with fibrosis. Our data suggest that HSP27 plays a key role in the pathophysiology of myelofibrosis and represents a new potential therapeutic target for patients with myeloproliferative neoplasms.
Assuntos
Proteínas de Choque Térmico HSP27/genética , Janus Quinase 2/genética , Oligonucleotídeos/farmacologia , Mielofibrose Primária/tratamento farmacológico , Mielofibrose Primária/genética , Fator de Transcrição STAT5/genética , Animais , Células da Medula Óssea/imunologia , Células da Medula Óssea/patologia , Transplante de Medula Óssea , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Células HEK293 , Proteínas de Choque Térmico HSP27/imunologia , Humanos , Janus Quinase 2/imunologia , Células K562 , Leucócitos/efeitos dos fármacos , Leucócitos/imunologia , Leucócitos/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Terapia de Alvo Molecular , Mutação , Mielofibrose Primária/imunologia , Mielofibrose Primária/patologia , Fator de Transcrição STAT5/imunologia , Trombopoetina/genética , Trombopoetina/imunologia , Transdução Genética , Irradiação Corporal TotalAssuntos
Aneuploidia , Fator Estimulador de Colônias de Granulócitos/efeitos adversos , Mobilização de Células-Tronco Hematopoéticas/métodos , Células-Tronco Hematopoéticas/efeitos dos fármacos , Leucemia/patologia , Adulto , Antígenos CD34/metabolismo , Divisão Celular , Feminino , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/fisiologia , Humanos , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
Chronic myelomonocytic leukemia (CMML) is a rare clonal hematopoietic disorder that can also involve the skin. The histopathology of these skin lesions is not clearly defined, and few data are available in the literature. To better understand tumoral skin involvements in CMML we carried out an extensive, retrospective clinicopathologic study of 42 cases selected from the database of the French Study Group of Cutaneous Lymphomas. On the basis of clinical data, morphology, and phenotype we identified 4 clinicopathologic profiles representing 4 distinct groups. The first group comprised myelomonocytic cell tumors (n=18), exhibiting a proliferation of granulocytic or monocytic blast cells, which were CD68 and/or MPO positive but negative for dendritic cell markers. The second group comprised mature plasmacytoid dendritic cell tumors (n=16), denoted by a proliferation of mature plasmacytoid dendritic cells, which were CD123, TCL1, and CD303 positive but CD56, CD1a, and S100 negative. The third group comprised blastic plasmacytoid dendritic cell tumors (n=4), characterized by a proliferation of monomorphous medium-sized blast cells, which were CD4, CD56, CD123, TCL1 positive but CD1a and S100 negative. The fourth group consisted of a putatively novel category of tumor that we named blastic indeterminate dendritic cell tumors (n=4), distinguished by a proliferation of large blast cells that not only exhibited monocytic markers but also the dendritic markers CD1a and S100. These 4 groups showed distinctive outcomes. Finally, we showed, by fluorescence in situ hybridization analysis, a clonal link between bone marrow disease and skin lesions in 4 patients. Herein, we have described a novel scheme for pathologists and physicians to handle specific lesions in CMML, which correspond to a spectrum of myelomonocytic and dendritic cell proliferations with different outcomes. A minimal panel of immunohistochemical markers including CD68, CD1a, S100, Langerin, and CD123 is necessary to make the correct classification in this spectrum of cutaneous CMML tumors, in which dendritic cell lineage plays an important role.