- B-lineage acute lymphoblastic leukemia (B-ALL) arises by malignant transformation of a progenitor (pre-B) cell. Cure rates in adults remain low and treatment is complicated by support provided by the microenvironment to the leukemic cells, indicating an urgent need to better understand the factors that promote their survival. We found that B-cell-activating factor (BAFF) and its receptor BAFF-R are important for ALL survival. Both Philadelphia chromosome (Ph)- positive and Ph-negative ALL samples tested were positive for high BAFF-R cell surface expression. Recombinant BAFF supported survival of the ALL cells in the absence of stroma, and it significantly attenuated the rate of apoptosis caused by exposure to nilotinib, a drug used therapeutically to treat Ph-positive ALLs. In this proposal, we will investigate the signaling pathways elicited by BAFF, role of BAFF in mediating drug resistance and finally how we can target BAFF-R or BAFF signaling for specific killing of ALL cells. We already published the effectiveness of fusion toxin rGel/BLyS in killing ALL cells. We propose to use a novel afucosylated BAFF-R antibody to mediate antibody dependent cytotoxicity (ADCC) using allogenic or autologous natural killer (NK) cells.
Acute Lymphoblastic Leukemia (ALL) is a type of cancer caused by accumulation of white blood cells in the body. In the United States, about 3000 new cases of ALL are identified every year, mostly children aged 2-8 years. A key issue in the treatment of ALL is the development of resistance to chemotherapeutic drugs. Our preliminary data shows that a protein named B cell activating factor (BAFF) and its receptor (BAFF-R) are found on the surface of ALL cells and not on its normal counterparts. Addition of BAFF protected ALL cells from chemotherapy induced cell death. Hence, we hypothesize that BAFF mediate drug resistance in ALL cells. We propose to study the mechanism by which BAFF protects ALL cells and design novel therapeutic methods targeting BAFF and BAFF-R to specifically kill ALL cells, without affecting normal cells.
| Asthana, Abhishek; Ramakrishnan, Parameswaran; Vicioso, Yorleny et al. (2018) Hexosamine Biosynthetic Pathway Inhibition Leads to AML Cell Differentiation and Cell Death. Mol Cancer Ther 17:2226-2237 |
