LIGHT/LTβR signaling regulates self-renewal and differentiation of hematopoietic and leukemia stem cells

Abstract

The production of blood cells during steady-state and increased demand depends on the regulation of hematopoietic stem cell (HSC) self-renewal and differentiation. Similarly, the balance between self-renewal and differentiation of leukemia stem cells (LSCs) is crucial in the pathogenesis of leukemia. Here, we document that the TNF receptor superfamily member lymphotoxin-β receptor (LTβR) and its ligand LIGHT regulate quiescence and self-renewal of murine and human HSCs and LSCs. Cell-autonomous LIGHT/LTβR signaling on HSCs reduces cell cycling, promotes symmetric cell division and prevents primitive HSCs from exhaustion in serial re-transplantation experiments and genotoxic stress. LTβR deficiency reduces the numbers of LSCs and prolongs survival in a murine chronic myeloid leukemia (CML) model. Similarly, LIGHT/LTβR signaling in human G-CSF mobilized HSCs and human LSCs results in increased colony forming capacity in vitro. Thus, our results define LIGHT/LTβR signaling as an important pathway in the regulation of the self-renewal of HSCs and LSCs.

LTβR overexpression promotes plasma cell accumulation

“…Multiple cell types in mouse and human BM express LTα1β2 and Tnfrsf14 (LIGHT) ( Immgen.org ; HCA BM viewer). Moreover, there is evidence for LTβR signaling in the BM acting to influence granulocyte metabolism [ 25 ], HSC maintenance [ 26 ], and mesenchymal cells [ 27 ]. As well as LTβR, MM can strongly OE CD40 and TACI (TNFRSF13B) [ 7 , 8 ].…”

IL-33–ST2 signaling promotes stemness in subtypes of myeloid leukemia cells through the Wnt and Notch pathways

“…Murine colony-forming cell (CFC) assays were performed as described before ( 78 ). Briefly, 2 × 10 4 to 1 × 10 5 FACS-purified leukemia blasts from AE9a BL/6 and ST2 −/− mice or 1 × 10 3 LSCs from BL/6 and ST2 −/− CML mice were cultured overnight in 100 μl of IMDM 10% (Iscove’s modified Dulbecco’s medium supplemented with 10% FCS, 1% penicillin/streptomycin, and 1% l -glutamine), supplemented with recombinant murine stem cell factor (rmSCF; 50 ng/ml), recombinant murine FMS-like tyrosine kinase 3 ligand (rmFLTL-3; 50 ng/ml), rmIL-3 (10 ng/ml), rhIL-6 (10 ng/ml), and rmGM-CSF (recombinant murine granulocyte-macrophage colony-stimulating factor) (only used for AE9a blasts, 10 ng/ml), in the absence or presence of rmIL-33 (10 ng/ml).…”

Signaling pathways governing the behaviors of leukemia stem cells

“…The LTβR pathway in combination with LIGHT induced the colony-forming capacity in human G-CSF mobilized HSCs and human LSCs. 167 The LIGHT/LTβR pathway has been reported to modulate LSCs' and HSCs' quiescence and self-renewal through decreasing cell proliferation and symmetric cell division over asymmetric ones. Since asymmetric division resulted in stem cell differentiation, LIGHT/LTβR targeting may suggest a promising insight to facilitate differentiation and eradicate LSCs.…”

“…Since asymmetric division resulted in stem cell differentiation, LIGHT/LTβR targeting may suggest a promising insight to facilitate differentiation and eradicate LSCs. 108 , 167 …”