RESUMEN
A role of endothelial cells in the survival of CLL cells during extravasation is presently unknown. Herein we show that CLL cells but not normal B cells can receive apoptotic signals through physical contact with TNF-α activated endothelium impairing survival in transendothelial migration (TEM) assays. In addition, the CLL cells of patients having lymphadenopathy (LApos) show a survival advantage during TEM that can be linked to increased expression of α4 and αL integrin chains. Within this context, ephrinA4 expressed on the surface of CLL cells sequestrates integrins and inactivates them resulting in reduced adhesion and inhibition of apoptotic/survival signals through them. In agreement, ephrinA4 silencing resulted in increased survival of CLL cells of LApos patients but not LA neg patients. Similarly was observed when a soluble ephrinA4 isoform was added to TEM assays strongly suggesting that accumulation of this isoform in the serum of LApos patients could contribute to CLL cells dissemination and survival in vivo. In supporting, CLL lymphadenopathies showed a preferential accumulation of apoptotic CLL cells around high endothelial venules lacking ephrinA4. Moreover, soluble ephrinA4 isolated from sera of patients increased the number and viability of CLL cells recovered from the lymph nodes of adoptively transferred mice. Finally, we present evidence suggesting that soluble ephrinA4 mediated survival during TEM could enhance a transcellular TEM route of the CLL cells. Together these findings point to an important role of ephrinA4 in the nodal dissemination of CLL cells governing extravasation and survival.
Asunto(s)
Apoptosis , Antígeno CD11a/metabolismo , Supervivencia Celular , Efrina-A4/metabolismo , Integrina alfa4/metabolismo , Leucemia Linfocítica Crónica de Células B/patología , Anciano , Anciano de 80 o más Años , Animales , Linfocitos B/fisiología , Células Cultivadas , Técnicas de Cocultivo , Endotelio/metabolismo , Efrina-A4/sangre , Efrina-A4/genética , Femenino , Células Endoteliales de la Vena Umbilical Humana , Humanos , Leucemia Linfocítica Crónica de Células B/sangre , Ganglios Linfáticos/patología , Metástasis Linfática , Masculino , Ratones , Ratones Endogámicos BALB C , Persona de Mediana Edad , Isoformas de Proteínas/sangre , Isoformas de Proteínas/metabolismo , Interferencia de ARN , ARN Interferente Pequeño/metabolismo , Organismos Libres de Patógenos Específicos , Migración Transendotelial y Transepitelial , Células Tumorales Cultivadas , Factor de Necrosis Tumoral alfa/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
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Asunto(s)
Femenino , Humanos , Masculino , Enfermedades Mielodisplásicas-Mieloproliferativas/diagnóstico , Enfermedades Mielodisplásicas-Mieloproliferativas/epidemiología , Enfermedades Mielodisplásicas-Mieloproliferativas/genética , Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/epidemiología , Neoplasias Hematológicas/genética , Enfermedades Mielodisplásicas-Mieloproliferativas/etiología , Neoplasias Hematológicas/clasificación , Neoplasias Hematológicas/etiologíaAsunto(s)
Leucemia Linfocítica Crónica de Células B/complicaciones , Linfoma no Hodgkin/complicaciones , Trastornos Mieloproliferativos/complicaciones , Adulto , Anciano , Biomarcadores de Tumor/genética , Marcadores Genéticos , Humanos , Janus Quinasa 2/genética , Leucemia Linfocítica Crónica de Células B/genética , Linfoma no Hodgkin/genética , Masculino , Persona de Mediana Edad , Mutación , Trastornos Mieloproliferativos/genética , Cromosoma Filadelfia , Proteínas Proto-Oncogénicas c-kit/genéticaRESUMEN
We have characterized the molecular changes underlying the transformation of a JAK2V617F+-myelofibrosis with trisomy 8, into a JAK2V617F-negative leukemia. Leukemic clone did not carry JAK2V617F mutation, but showed ASXL1 mutation (R693X). This mutation was identified in a low percentage at diagnosis by next-generation sequencing. Using this technology in serial specimens during the follow-up, we observed a progressive expansion of the ASXL1-mutated minor clone, whereas the JAK2V617F+-clone carrying trisomy 8 decreased. Hematologic progression occurred simultaneously with an ASXL1-R693X-negative lung-cancer. This is the first report showing a clear association between the expansion of an ASXL1-mutated clone and the leukemic transformation of myelofibrosis.