Galectins as regulators of cell survival in the leukemia niche

Abstract

The microenvironment within the bone marrow (BM) contains support cells that promote leukemia cell survival and suppress host anti-tumor defenses. Galectins are a family of beta-galactoside binding proteins that are critical components in the tumor microenvironment. Galectin 1 (LGALS1) and Galectin 3 (LGALS3) as regulators of RAS signaling intracellularly and as inhibitors of immune cells extracellularly are perhaps the best studied members for their role in leukemia biology. Interest in Galectin 9 (LGALS9) is growing as this galectin has been identified as an immune checkpoint molecule. LGALS9 also supports leukemia stem cells (LSCs) though a mechanism of action is not clear. LGALS1 and LGALS3 each participate in a diverse number of survival pathways that promote drug resistance by supporting pro-tumor molecules such BCL2, MCL-1, and MYC and blocking tumor suppressors like p53. Acute myeloid leukemia (AML) BM mesenchymal stromal cells (MSC) have protein signatures that differ from healthy donor MSC. Elevated LGALS3 protein in AML MSC is associated with refractory disease/relapse demonstrating that MSC derived galectin impacts patient survival. LGALS3 is a critical determining factor whether MSC differentiate into adipocytes or osteoblasts so the galectin influences the cellular composition of the leukemia niche. Both LGALS3 and LGALS1 when secreted can suppress immune function. Both galectins can induce apoptosis of T cells. LGALS3 also modulates T cell receptor endocytosis and impairs interferon mediated chemokine production by binding glycosylated interferon. LGALS3 as a TIM3 binding partner acts to suppress T cell function. Galectins also impact leukemia cell mobilization and may participate in homing mechanisms. LGALS3 participates in transport mechanism of integrins, receptors, and other molecules that control cell adhesion and cell:cell interactions. The diversity of these various functions demonstrate the importance of these galectins in the leukemia niche. This review will cover the role of LGALS1, LGALS3, and LGALS9 in the various processes that are critical for maintaining leukemia cells in the tumor microenvironment.