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 dual 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 human BCP-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 these two Galectins at both locations would decrease microenvironmental protection and reduce BCP-ALL persistence in the protective bone marrow niche after chemotherapy.