TY - JOUR T1 - The mitoNEET ligand NL-1 mediates anti-leukemic activity in drug resistant B-cell acute lymphoblastic leukemia JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.118.255984 SP - jpet.118.255984 AU - Werner J Geldenhuys AU - Rajesh R Nair AU - Debra Piktel AU - Karen H Martin AU - Laura F Gibson Y1 - 2019/01/01 UR - http://jpet.aspetjournals.org/content/early/2019/04/22/jpet.118.255984.abstract N2 - Disease relapse in B-cell acute lymphoblastic leukemia (ALL), either due to development of acquired resistance after therapy or because of de novo resistance, remains a therapeutic challenge. In the present study, we have developed a cytarabine (Ara-C) resistant REH cell line (REH/Ara-C) as a chemoresistance model. REH/Ara-C (a) was not cross-resistant to vincristine or methotrexate; (b) showed a similar proliferation rate and cell surface marker expression as parental REH; (c) demonstrated decreased chemotaxis towards bone marrow stromal cells (BMSC); and (iv) expressed higher transcript levels of cytidine deaminase (CDA) and mitoNEET (CISD1) than the parental REH cell line. Based on these findings, we tested NL-1, a mitoNEET inhibitor, which induced a concentration-dependent decrease in cell viability with a comparable IC50 in REH and REH/Ara-C. Furthermore, NL-1 decreased cell viability in six different ALL cell lines and showed inhibitory activity in a hemosphere assay. NL-1 also impaired the migratory ability of leukemic cells, irrespective of the chemoattractant used, in a chemotaxis assay. More importantly, NL-1 showed specific activity in inducing death in a drug resistant population of leukemic cells within a co-culture model that mimicked the acquired resistance and de novo resistance observed in the BM of relapsed patients. Subsequent studies indicated that NL-1 mediates autophagy, and inhibition of autophagy partially decreased NL-1-induced tumor cell death. Finally, NL-1 showed anti-leukemic activity in an in vivo mouse ALL model. Taken together, our study demonstrates that mitoNEET has potential as a novel anti-leukemic drug target in treatment refractory or relapsed ALL. ER -