Nora Heisterkamp Lab Research Highlights
Because little is known concerning the glycome of leukemias, we performed integrated glycomic /transcriptomic /proteomic analysis on primary B-cell precursor MLL-r leukemia samples. These were compared to normal B-cell precursors from bone marrow, and significant differences were identified between the leukemic and normal cells. These studies were performed in an ongoing collaboration with scientists at the Institute for Glycomics at Griffith University in Australia.
Oliveira, T., Zhang, M., Joo, E.J., Abdel-Azim, H., Chen, C.-W., Yang, L., Chou, C.-H., Qin, X., Chen, J., Alagesan, K., Almeida, A., Jacob, F., Packer, N.H., von Itzstein, M., *Heisterkamp, N., & *Kolarich, D. Glycoproteome remodeling in MLL-rearranged B-cell precursor acute lymphoblastic leukemia. Theranostics 11(19): 9519-9537, 2021.
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When BCP-ALL cells develop insensitivity to drugs while protected by the presence of stromal cells, the leukemia cells have changes in the expression of many genes. One class of genes related to inflammatory processes includes a carbohydrate-binding protein called Galectin-3. We studied how Galectins are produced endogenously in BCP-ALL cells as well as Galectins secreted by bone marrow stromal cells to protect BCP-ALL cells and promote their survival when treated with therapeutic drugs. We found that Galectin-3 is one of the molecular mediators of two-way communication between the leukemia cells and their microenvironment.
Tarighat, S.S., Fei, F., Joo, E.J., Abdel-Azim, H., Yang, L., Geng, H., Bum-Erdene, K., Grice, D.I., von Itzstein, M., Blanchard, H., & Heisterkamp, N.. Overcoming microenvironment-mediated chemoprotection through stromal Galectin-3 inhibition in acute lymphoblastic leukemia. Int J Mol Sci, 22(22):12167, 2021.
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Based on its relevance to leukemia cell survival, we are also interested in the therapeutic development of Galectin-3 inhibitors. Galectin-3 contains a unique N-terminal domain (NTD) and a carbohydrate-binding domain (CRD) located at the C-terminal end. We tested different novel carbomimetics as inhibitors of the CRD, finding compounds that are highly specific for Galectin-3. The NTD is an intrinsically disordered region that adopts multiple conformations under physiological conditions and is highly dynamic. This would make the NTD a very difficult drug target. However, in collaboration with the Department of Computational and Quantitative Medicine at City of Hope critical Galectin-3 residues were identified that could be used for the rational design of a selective small molecule peptide inhibitor. Collectively, these findings indicate that Galectin-3 regulates BCP-ALL cell responses to chemotherapy through the interactions between leukemia cells and the stroma, and show that Galectin-3 can be inhibited to sensitize leukemia cells to chemotherapy.
Bum-Erdene, K., Collins, P.M., Hugo, M.W., Tarighat, S.S., Fei, F., Kishor, C., Leffler, H., Nilsson, U.J., Groffen, J., Grice, D.I., Heisterkamp, N., & Blanchard, H. Novel selective galectin-3 antagonists are cytotoxic to acute lymphoblastic leukemia. J. Med. Chem. 65, 5975-5989, 2022.
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- The SDF1âº-CXCR4 axis is a major chemo-attractant mechanism for pre-B ALL cells that promotes migration and adhesion to stromal cells. Our studies showed that inhibition of binding of SDF1⺠to CXCR4 with small molecule inhibitors chemo-sensitizes the leukemia cells in tissue culture and in mouse models.
- An important step towards the development of new therapies for cancer is identifying cell surface molecules that have restricted expression or ideally have expression only on the target cancer cell. Our studies were the first to identify expression of the BAFF-R on the surface of many pre-B ALL samples and to make use of this to explore different forms of therapy including the application of NK cells.
- Galectins are carbohydrate-binding proteins with immune-modulatory properties. We discovered that when pre-B ALL cells develop insensitivity to drugs when protection is provided by the presence of stromal cells, the leukemia cells have radical changes in the expression of many genes related to inflammatory processes. One of these is Galectin-3. However, under non-stressed conditions, pre-B ALL cells do not synthesize their own Galectin-3 and all the Galectin-3 present in and on these cells is provided by the protective stromal cells. Thus Galectin-3 is one of the molecular mediators of a two-way communication between the leukemia and the microenvironment.