Células microambientais não malignas colaboram no desenvolvimento de leucemia

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Células microambientais não malignas colaboram no desenvolvimento de leucemia

Sexta, 11.01.2019

Investigadores do CBMR (Faro) e do i3S (Porto) descobrem que células epiteliais não malignas colaboram no desenvolvimento de leucemia de linfócitos T. Este estudo mostrou que num modelo animal os linfócitos T malignos surgem no timo, o órgão formador de linfócitos T, sofrendo aquele uma série de alterações celulares à medida que a doença progride. Uma análise detalhada revelou que as células epiteliais de linfomas tímicos apresentam características fenotípicas distintas das de timos saudáveis. A observação que os murganhos transgénicos TEL-JAK2 com expressão reduzida de FoxN1, um fator de transcrição vital para as células epiteliais do timo, desenvolviam leucemia de forma mais lenta revelou a importância destas células. Estes estudos indicam que o melhor conhecimento dos fatores microambientais que favorecem o desenvolvimento e progressão desta doença poderão revelar novos alvos terapêuticos.

Marinella N. Ghezzo (CBMR, Faro), Mónica T. Fernandes (CBMR, Faro), Ivette Pacheco-Leyva (i3S, Porto), Pedro M. Rodrigues (i3S, Porto), Rui S. Machado (CBMR, Faro), Marta A.S. Araújo (i3S, Porto), Ravi K. Kalathur (CBMR, Faro), Matthias E. Futschik (CBMR, Faro; CCMAR, Faro; ITSMED, Plymouth), Nuno L. Alves (i3S, Porto), Nuno R. dos Santos (CBMR, Faro; i3S, Porto),

T-cell acute lymphoblastic leukemia (T-ALL) and T-lymphoblastic lymphomas (T-LBL) are aggressive malignancies of thymocytes. The role of thymic microenvironmental cells and stromal factors in thymocyte malignant transformation and T-ALL development remains little explored. Here, using the TEL-JAK2 transgenic (TJ2-Tg) mouse model of T-ALL/LBL, which is driven by constitutive JAK/STAT signaling and characterized by the acquisition of Notch1 mutations, we sought to identify stromal cell alterations associated with thymic leukemogenesis. Immunofluorescence analyses showed that thymic lymphomas presented epithelial areas characterized by keratin (Krt) 5 and Krt8 expression, adjacently to epithelial-free areas negative for Krt expression. Both areas contained abundant laminin (extracellular matrix) and ER-TR7+ (fibroblasts) CD31+ (endothelial) and CD11c+ (dendritic) cells. Besides Krt5, Krt-positive areas harbored medullary thymic epithelial cells (TECs) labeled by Ulex europaeus agglutinin-1. By performing flow cytometry and RNA sequencing analyses of thymic lymphomas, we observed an enrichment in medullary TEC markers in detriment of cortical TEC markers. To assess whether TECs are important for T-ALL/LBL development, we generated TJ2-Tg mice heterozygous for the FoxN1 transcription factor nude null mutation (Foxn1+/nu). Strikingly, in TJ2-Tg;Foxn1+/nu compound mice, both emergence of malignant cells in preleukemic thymi and overt T-ALL onset were significantly delayed. Moreover, in transplantation assays, leukemic cell expansion within the thymus of recipient Foxn1+/nu mice was reduced as compared with control littermates. Since thymopoesis is largely normal in Foxn1+/nu mice, these results indicate that FoxN1 haploinsufficiency in TECs has a more profound impact in thymic leukemogenesis.