SummaryLymphotoxin-mediated activation of the lymphotoxin-b receptor (LTbR; LTBR) has been implicated in cancer, but its role in T-cell acute lymphoblastic leukaemia (T-ALL) has remained elusive. Here we show that the genes encoding lymphotoxin (LT)-a and LTb (LTA, LTB) are expressed in T-ALL patient samples, mostly of the TAL/LMO molecular subtype, and in the TEL-JAK2 transgenic mouse model of cortical/mature T-ALL (Lta, Ltb). In these mice, expression of Lta and Ltb is elevated in early stage T-ALL. Surface LTa 1 b 2 protein is expressed in primary mouse T-ALL cells, but only in the absence of microenvironmental LTbR interaction. Indeed, surface LT expression is suppressed in leukaemic cells contacting Ltbr-expressing but not Ltbr-deficient stromal cells, both in vitro and in vivo, thus indicating that dynamic surface LT expression in leukaemic cells depends on interaction with its receptor. Supporting the notion that LT signalling plays a role in T-ALL, inactivation of Ltbr results in a significant delay in TEL-JAK2-induced leukaemia onset. Moreover, young asymptomatic TEL-JAK2;Ltbr À/À mice present markedly less leukaemic thymocytes than agematched TEL-JAK2;Ltbr +/+ mice and interference with LTbR function at this early stage delayed T-ALL development. We conclude that LT expression by T-ALL cells activates LTbR signalling in thymic stromal cells, thus promoting leukaemogenesis.
Two main NF-κB signaling pathways, canonical and noncanonical, performing distinct functions in organisms have been characterized. Identification of mutations in genes encoding components of these NF-κB signaling pathways in lymphoid malignancies confirmed their key role in leukemogenesis. T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy of thymocytes that despite significant therapeutic advances can still be fatal. Although mutations in NF-κB genes have not been reported in T-ALL, NF-κB constitutive activation in human T-ALL and in acute T-cell leukemia mouse models has been observed. Although these studies revealed activation of members of both canonical and noncanonical NF-κB pathways in acute T-cell leukemia, only inhibition of canonical NF-κB signaling was shown to impair leukemic T cell growth. Besides playing an important pro-oncogenic role in leukemic T cells, NF-κB signaling also appears to modulate T-cell leukemogenesis through its action in microenvironmental stromal cells. This article reviews recent data on the role of these transcription factors in T-ALL and pinpoints further research crucial to determine the value of NF-κB inhibition as a means to treat T-ALL.
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy 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, 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 5 and keratin 8 expression, adjacently to keratin-negative, epithelialfree areas. Both keratin-positive and -negative areas stained conspicuously with ER-TR7 (a fibroblast marker), laminin, and CD31 (an endothelial cell marker). Besides keratin 5, keratin-positive areas were also labeled by the Ulex Europaeus agglutinin-1 medullary thymic epithelial cell (TEC) marker. To assess whether TECs are important for T-ALL development, we generated TJ2-Tg mice heterozygous for the FoxN1 transcription factor nude null mutation. In contrast to nude homozygous mice, which lack thymus and thymocytes, heterozygous mutant mice present only mild thymocyte maturation defects. In TJ2-Tg;Foxn1 +/nu compound mice both emergence of malignant cells in pre-leukemic thymi and overt T-ALL onset were significantly delayed. Moreover, in transplantation assays leukemic cell expansion in the thymus of recipient Foxn1 +/nu mice was reduced as compared to control littermates.These results indicate that FoxN1 insufficiency impairs specifically thymic leukemogenesis but not thymocyte development. SummaryIn a mouse model of T-ALL, several cellular alterations were detected in thymic lymphomas, including altered epithelial distribution and increased proportion of fibroblasts or endothelial cells. Reduced dosage of FoxN1, a thymic epithelial transcription factor, delayed leukemogenesis in these mice.not peer-reviewed)
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