Lymphotoxin-β receptor in microenvironmental cells promotes the development of T-cell acute lymphoblastic leukaemia with cortical/mature immunophenotype

Abstract

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.

FoxN1-dependent thymic epithelial cells promote T-cell leukemia development

“…In contrast with these data, we found that loss of a single Foxn1 allele hindered both the onset of spontaneous TEL-JAK2-induced leukemia/lymphoma and the thymic expansion of leukemic cells in recipient mice. Since leukemogenesis in TJ2-Tg mice is initiated in the thymus (33,37) and only TECs express Foxn1, we conclude that the delayed leukemogenesis in heterozygotes is caused by FoxN1-mediated defects dependent on these cells. Foxn1 haploinsufficiency was shown to cause a moderate reduction in thymic weight of pre-puberty mice (under 5 weeks) of different outbred and inbred strains (28,44,45).…”

“…However, thymi from TJ2-Tg;Foxn1 +/nu mice displayed a significantly lower percentage of CD8 + CD25 + cells than TJ2-Tg;Foxn1 +/+ thymi (7.8-fold difference; Figure 3F). At this age, leukemic cells are detectable mainly in the thymus (33). Although low percentages of CD8 + CD25 + cells could be detected in the blood, bone marrow and spleen of some mice, those were not significantly different among Foxn1 genotypes ( Figure 3F and not shown).…”

“…To investigate whether Foxn1 haploinsufficiency delayed the early stages of leukemogenesis at the cellular level, we monitored disease emergence in young pre-disease TJ2-Tg mice through detection of CD8 + CD25 + leukemic cells within total thymocytes, ( Figure 3D). At this age, leukemic cells can be detected in TJ2-Tg thymi without significant organ enlargement (33). Indeed, thymic weight in the analyzed Foxn1 +/+ and Foxn1 +/nu TJ2-Tg mice was not significantly different and it did not correlate with the percentage of detected CD8 + CD25 + leukemic cells ( Figure 3E).…”

“…The thymic molecular and cellular players involved in stromal support of thymocyte leukemogenesis have only recently began to be explored. Our group has reported that stromal cell inactivation of the RelB transcription factor and the TNF receptor superfamily member lymphotoxin-β receptor (LTβR), both components of the noncanonical NF-κB signaling pathway, delayed leukemia development in the TEL-JAK2 transgenic (TJ2-Tg) mouse model (32,33). Recently, Triplett and colleagues (34) found in another T-ALL mouse model that IGF1R was highly expressed by malignant cells and that high IGF-1 secretion by tumor-associated thymic dendritic cells (DCs) favored leukemic cell survival.…”

Erratum

“…Errors have been identified in the Figure 1 text citations of Fernandes et al () on page 742, column 1.…”