Targeting NLRP1-CCL8 axis in the leukaemic niche suppresses AML via inhibition of PI3K-AKT signalling.

Abstract

Bone marrow microenvironment not only plays a key role in supporting normal haematopoiesis but also plays an important role in regulating the progression of acute myelogenous leukaemia (AML). Targeting the bone marrow microenvironment will provide new targets for AML treatment. However, until now, the mechanism by which the bone marrow microenvironment promotes AML progression remains obscure. Our previous studies have found that the bone marrow microenvironment Nucleotide-binding Oligomerization Domain (NOD)-Leucine Rich Repeat (LRR)-containing Receptors (NLR) family pyrin domain containing 1 (NLRP1) plays an important role in the regulation of bone marrow endothelial cells, mesenchymal stem cell (MSC) cells and haematopoiesis, but the effect of the bone marrow microenvironment NLRP1 on AML has not been addressed. In this study, we found that niche Nlrp1 KO inhibited AML disease progression and leukaemia stem cell activity. Moreover, Nlrp1 was expressed in the bone marrow microenvironment, especially in MSC. Nlrp1 knockout in MSC inhibits the growth and proliferation of co-cultured leukaemia cells, which is related to Nlrp1 KO inhibition of Ccl8 secretion in MSC and CCL8/CCR1-mediated PI3K-AKT activation in AML cells. Our study highlights the critical role of niche NLRP1 in AML and it could be a therapeutic target for AML.