NF-κB-Dependent Activation of the Proteasome Components, PSMD1 and PSMD3, As a Mechanism of Resistance to Imatinib

• Published in: Blood 2019-11, Vol.134 (Supplement_1), p.2923-2923
• Main Authors: Olivas, Idaly Maria, Lara, Joshua, Ellwood, Rebecca, Ripoll Fiol, Carme, Rubio, Andres J, Bencomo, Alfonso Enrique, Gonzalez, Mayra Alejandra, Nteliopoulos, Georgios, Reid, Alistair, Milojkovic, Dragana, Apperley, Jane, Sorouri Khorashad, Jamshid, Eiring, Anna M.
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2019-126963

Tyrosine kinase inhibitors (TKIs) targeting BCR-ABL1 are remarkably effective therapies in chronic myeloid leukemia (CML). Despite clinical success, TKIs do not target the CML leukemic stem cell (LSC), and the majority of patients must be treated for life to maintain remission. Our previous work has shown that BCR-ABL1-independent resistance is driven by STAT3 in CML stem/progenitor cells (Eiring et al. Leukemia 2015). Unexpectedly, RNA-sequencing on TKI-resistant K562 cells (K562-R) versus parental controls (K562-S) revealed that resistance is not associated with STAT3-mediated transcription, but is rather reminiscent of TNFa signaling via NF-κB (p=0.024). Nucleocytoplasmic fractionation confirmed these findings, demonstrating higher levels of phospho-NF-κB in the nucleus of CD34+ cells from TKI-resistant patients (n=3) compared to newly diagnosed CML patients (n=2) or normal individuals (n=2). Surprisingly, ELISA results revealed that K562-R cells do not produce autonomous TNFa, but they do produce IL-6 (p