Fig. 2.

Nrf2 signaling pathway in the malignant cells. In normal conditions, three E3 ubiquitin ligases suppress Nrf2 by forming an inhibitory complex (Keap1-CUL3-RBX1, β-TrCP-SKP1-CUL1-RBX1, and HRD1). However, in leukemic cells or under oxidative stress, Nrf2 is released from this negative regulator and activates the transcription of target genes after forming heterodimers with sMAF. Moreover, Nurse-like cells produce Baff in the malignant cell microenvironment that induces ROR1 and Baff receptor expression on the malignant cells, leading to an inflammatory cytokine (NF-κB, IL6, TNF) increase inside the leukemic cells and recruitment of P65p, which binds to Keap1, and releases Nrf2 from the Keap1-CUL3-RBX1 inhibitory complex