AML-044: LGALS1 Acts as a Pro-Survival Molecule in AML

Abstract

Context Galectin 1 (LGALS1) participates in diverse survival pathways that support many pro-tumor molecules, especially those regulated by RAS. LGALS1 regulates hematopoietic cell differentiation, so it is not surprising that LGALS1 plays a role in many hematologic malignancies such as acute lymphoblastic leukemia (ALL). However, LGALS1's role in acute myeloid leukemia (AML) is not well defined. Objective We previously found suppression of LGALS1 in AML cell lines sensitized cells to BCL2 inhibitor ABT-737. In this study, we examine the role of LGALS1 in AML. We used an in vivo murine OCI-AML3 xenograft model with control and LGALS1 shRNA cells to test if reduction of LGALS1 affects survival. Gene expression profiling using RNASeq was performed using control and LGALS1 shRNA of p53 WT OCI-AML3 and p53 null THP-1 cells. Patients Analysis of mRNA expression by RNA Seq in AML patients was performed on TCGA AML cohort from NEJM 2013 using cBioPortal. Results Mice with OCI-AML3 cells with LGALS1 shRNA survived significantly longer than control group. There was no difference in leukemia burden in blood but mice bearing OCI-AML3 cells with LGALS1 shRNA showed significant reduction of cells infiltrating the spleen. RNASeq data from THP-1 and OCI-AML3 control and LGALS1 shRNA transductants reveal distinct differences between the two cell lines in number of genes affected, pathways affected, expression of oncogenes, and in transcription factors involved. The p53 pathway is prominent in OCI-AML3 cells while focal adhesion kinase pathway is prominent in THP-1 cells. Of the few genes common to both cell lines, asparagine regulators were reduced. Asparaginase is a common therapy in ALL, so LGALS1 regulation of asparagine metabolism may be important in AML. Examination of LGALS1 mRNA in an AML patient population reveals elevated LGALS1 mRNA is associated with shorter disease-free survival and increased blasts in bone marrow. This data with the xenograft model data suggest LGALS1 may be important in the AML microenvironment. Conclusions Data presented here suggest LGALS1 plays important roles in diverse survival pathways, including p53 pathway, and LGALS1 regulates mobilization of leukemic cells from the leukemia niche. Therefore, a strategy targeting LGALS1 may benefit AML patients.