Treatment of B-cell precursor acute lymphoblastic leukemia with the Galectin-1 inhibitor PTX008

Helicia Paz, Eun Ji Joo, Chih Hsing Chou, Fei Fei, Kevin H. Mayo, Hisham Abdel-Azim, Haike Ghazarian, John Groffen, Nora Heisterkamp

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12 Scopus citations

Abstract

Background: Drug resistance of B-cell precursor acute lymphoblastic leukemia (BP-ALL) cells is conferred by both intrinsic and extrinsic factors, which could be targeted to promote chemo-sensitization. Our previous studies showed that Galectin-3, a lectin that clusters galactose-modified glycoproteins and that has both an intracellular and extracellular location, protects different subtypes of BP-ALL cells against chemotherapy. Galectin-1 is related to Galectin-3 and its expression was previously reported to be restricted to the MLL subtype of BP-ALL. Methods and results: Here, we report that Galectin-1 is expressed at different levels in and on different subclasses of BP-ALLs. Bone marrow plasma also contains high levels of Galectin-1. PTX008 is an allosteric inhibitor which inhibits Galectin-1 but not Galectin-3-mediated agglutination. The compound reduces migration of BP-ALL cells to CXCL12 and OP9 stromal cells and inhibits fibronectin-mediated adhesion. It also affects cell cycle progression of BCP-ALL cells. PTX008 is cytostatic for BP-ALL cells even when these are co-cultured with protective stroma, and can sensitize ALL cells to vincristine chemotherapy in vitro and in mice. Conclusions: PTX008 inhibits multiple functions that contribute to BP-ALL survival. The effects of Galectin-1 inhibition on both BP-ALL cell proliferation and migration suggest both the leukemia cells as well as the microenvironment that protects these cells may be targeted.

Original languageEnglish (US)
Article number67
JournalJournal of Experimental and Clinical Cancer Research
Volume37
Issue number1
DOIs
StatePublished - Mar 27 2018

Bibliographical note

Funding Information:
We thank Lu Wang for help with statistical analysis. Research reported in this publication includes work performed in the Analytical Cytometry Core at the Beckman Research Institute City of Hope, supported by the National Cancer Institute of the National Institutes of Health under award number P30CA33572.

Funding Information:
This study was supported by PHS NIH RO1 CA172040 and CA090321 (NH).

Keywords

  • Adhesion
  • Co-culture
  • Lymphoid neoplasia
  • Migration
  • Stroma

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