Cell-Intrinsic and Extrinsic Effects of Galectin-1 and Galectin-3 in B-Cell Precursor Acute Lymphoblastic Leukemia

Abstract

Acute lymphoblastic leukemias arising from the malignant transformation of B-cell precursors (BCP ALLs) are protected against chemotherapy by both intrinsic factors as well as by interactions with bone marrow stromal cells. Galectin-1 and Galectin-3 have overlapping expression patterns and potentially common functions in these cells. We used Galectin-1 and Galectin-3 double null mutant murine BCP ALL cells to examine the effect of loss endogenous Galectins. We also tested the effect of Galectin inhibition by use of plant-derived natural compounds GM-CT-01 and GR-MD-02 in human BCP ALL cells in co-culture with stroma. Transformed wild type and Galectin-1 x Galectin-3 double knockout BCP ALL cells were similar in immunophenotype and active intracellular signaling. However, compared to wild type cells, they showed impaired migration, significantly reduced proliferation and increased sensitivity to drug treatment. GM-CT-01 and GR-MD-02 attenuated intracellular signal transduction and sensitized the ALL cells to chemotherapy including vincristine and the targeted tyrosine kinase inhibitor nilotinib. Our data show endogenous and extracellular Galectins contribute positively to the growth and survival of BCP ALL cells. Strategies that would efficiently ablate both Galectins at both locations would decrease microenvironmental protection and reduce BCP ALL persistence in the protective bone marrow niche after chemotherapy.