Lab In The News
Fundamental Step Found in the Cellular Response to Stress Caused by Pathological and Pharmacological Insults
A new study conducted by researchers at The Wistar Institute revealed how a key protein residing in the endoplasmic reticulum (ER) helps cells respond to stress. This process is especially important for B cells to respond to severe stress conditions and their ability to produce antibodies.
The Hu Laboratory
The Hu laboratory studies endoplasmic reticulum (ER), which has critical functions in lipid synthesis, calcium storage and drug metabolism. The ER also contains complex machineries to fold, assemble, transport or – as the need arises - destruct many vital integral membrane growth receptors and secretory proteins. The Hu lab strives to better understand the complexity of the ER functions.
Anthony Tang, M.D., Ph.D.
Andong Shao, Ph.D.
The Hu lab studied the ER functions in B cells because differentiated B cells produce a dramatically expanded ER for the production and secretion of antibodies to fight infections. Misfolded antibodies are unavoidable byproducts in the ER upon massive production of antibodies, and they were believed to activate the XBP-1 transcription factor, which was arguably one of the most important factors in correcting protein misfolding problems and expanding the size of the ER. Thus, Hu's lab chose XBP-1 to peek into the biology of the ER. Our initial pursuit of the function of XBP-1 led to surprising conclusions that XBP-1 is not activated by misfolded antibodies and XBP-1 plays minimal role in correcting misfolded proteins in B cells. These conclusions were reached by disabling B cells of their capability in making antibodies and by deleting the XBP-1 gene from the B cells. Further investigation by the lab suggested that XBP-1 is activated by differentiation cues. This work revealed new roles for XBP-1 in regulating signal transduction through the B cell receptor; in regulating the expression of important transcription factors in B cells; in maintaining proper lipid synthesis and protein glycosylation in B cells; and in colonization of stimulated B cells into the bone marrow for sustention of antibody production.
Inspired by XBP-1’s roles in maintaining a homeostatic ER, the lab began to examine the role of XBP-1 in B-cell leukemia whose progression does not require dramatic ER expansion like that in multiple myeloma. The lab chose to use the TCL1 mouse model to study B-cell leukemia because ~90 percent of human chronic lymphocytic leukemia (CLL) patients express the TCL1 protein, and the overexpression of TCL1 in B cells leads to the development of CLL in mice. We showed that TCL1 oncoprotein associates with XBP-1 and turns on vital ER proteins to support leukemic growth. When the function of XBP-1 is genetically deleted in TCL1 mice, significantly slower leukemic progression is observed. The lab further developed inhibitors to target the expression of XBP-1 and established that blocking the expression of XBP-1 by specific small-molecule chemical inhibitors can stall malignant progression of leukemia in mice and induce apoptosis in primary human leukemic cells. Currently, the Hu lab continues to analyze the functions of ER proteins in malignant progression of leukemia using novel mouse models, in which we selectively deleted genes that encode critical ER-resident proteins that support the growth and survival of leukemia. The Hu lab is also generating new mouse models to expand the breadth of our investigation. The ultimate goal of this work is to contribute to the design of effective therapeutic approaches that target dysregulated ER functions for patients with leukemia and other malignancies.
Specific laboratory projects:
- Investigate IRE-1-interacting proteins to further understand how targeting the IRE-1/XBP-1 pathway can lead to stalled progression of CLL
- Investigate the roles of protein antigen and Toll-like receptor ligands in activating the ER stress response to promote leukemic progression
- Investigate the roles of protein misfolding in B-cell leukemia
Tang, C.H., Chang, S., Hu, C.C., et al. "Secretory IgM Exacerbates Tumor Progression by Inducing Accumulations of MDSCs in Mice." Cancer Immunol Res. 2018 Jun;6(6):696-710. doi: 10.1158/2326-6066.CIR-17-0582. Epub 2018 Apr 12.
Tang, C.H., Chang, S., Hu, C.C., et al. "Phosphorylation of IRE1 at S729 regulates RIDD in B cells and antibody production after immunization." J Cell Biol. 2018 May 7;217(5):1739-1755. doi: 10.1083/jcb.201709137. Epub 2018 Mar 6.
Tang, C.H., Zundell, J.A., Hu, C.C., et al. "Agonist-Mediated Activation of STING Induces Apoptosis in Malignant B Cells." Cancer Res. 2016 Apr 15;76(8):2137-52. doi: 10.1158/0008-5472.CAN-15-1885. Epub 2016 Mar 7.
Tang, C.H., Ranatunga, S., Hu, C.C., et al. "Inhibition of ER stress-associated IRE-1/XBP-1 pathway reduces leukemic cell survival." J Clin Invest. 2014 Jun;124(6):2585-98. doi: 10.1172/JCI73448. Epub 2014 May 8.
Ranatunga, S., Tang, C.H., Del Valle, J.R., et al. "Synthesis of novel tricyclic chromenone-based inhibitors of IRE-1 RNase activity." J Med Chem. 2014 May 22;57(10):4289-301. doi: 10.1021/jm5002452. Epub 2014 May 2.