DLL4 regulates NOTCH signaling and growth of T acute lymphoblastic leukemia cells in NOD/SCID mice

Abstract

Activation of the NOTCH pathway occurs commonly in T acute lymphoblastic leukemia (T-ALL) mainly due to mutations in NOTCH1 or alterations in FBW7 and is involved in the regulation of cell proliferation and survival. Since mutations hit different domains of the receptor, they are predicted to heterogeneously perturb ligand-induced NOTCH1 activity. Moreover, T-ALL cells also co-express NOTCH3 receptors which could be triggered by different ligands. In this study, we aimed to investigate the role of DLL4 in the regulation of NOTCH signaling in T-ALL cells in the context of different types of NOTCH1 mutation or wild-type NOTCH receptor, as well as the effects of DLL4 neutralization on T-ALL engraftment in mice. We found that NOTCH signaling can be stimulated in T-ALL cells in vitro by either human or murine DLL4 with heterogeneous effects, according to NOTCH1/FBW7 mutation status, and that these effects can be blocked by antibodies neutralizing DLL4, NOTCH1 or NOTCH2/3. In vivo, DLL4 is expressed in the spleen and the bone marrow (BM) of NOD/SCID mice bearing T-ALL xenografts as well as the BM of T-ALL patients. Importantly, DLL4 blockade impaired growth of T-ALL cells in NOD/SCID mice and increased leukemia cell apoptosis. These results show that DLL4 is an important component of the tumor microenvironment which contributes to the early steps of T-ALL cell growth.

Hedgehog pathway activation in T-cell acute lymphoblastic leukemia predicts response to SMO and GLI1 inhibitors

“…Despite the fact that human T-ALL cells harbor mutations that activate their proliferation and survival, it has been shown that they remain partially dependent on the presence of stimulatory ligands such as DLL4 and IL-7. 48,49 Thus, the stimulation of the TECs to produce such ligands, as observed in our study, would provide a benefit to the leukemia cell proliferation and survival.…”

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

“…interleukin 7 (IL7), IL18 and insulin‐like growth factor 1 (IGF1)], chemokines, Notch ligands (DLL4) and adhesion molecules (e.g. ICAM1) (Winter et al , ; Buonamici et al , ; Medyouf et al , ; Silva et al , ; Mirandola et al , ; Uzan et al , ; Minuzzo et al , ). Furthermore, our group has found that expression of the NF‐κB transcription factor RELB in non‐haematopoietic stromal cells contributes to the development of T‐ALL in a mouse model (dos Santos et al , ).…”

Endothelial cell regulation of salivary gland epithelial patterning

“…As IGFBP2 and IGFBP3 gave robust signals on the proteome array and have previously been identified as angiocrine factors (Remédio et al, 2012;Minuzzo et al, 2015;Rafii et al, 2016), we tested whether these factors can rescue epithelial patterning upon vasculature disruption using recombinant IGFBP2 or IGFBP3 added to SMG culture assays. In the SMG cell fractionation/ reconstitution assay, addition of recombinant IGFBP2 or IGFBP3 promoted both epithelial patterning (Fig.…”