BACH2 blockade confers drug-resistant properties to MCL by promoting plasmacytic differentiation. (A) BACH2^KO or BACH2^KO-OE MCL cells were treated with bortezomib for 24 hours. Cell viability was determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-dimethyltetrazolium bromide; 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assays. Controls were mock-transfected cells. Data are presented as the mean ± S.D. from 3 independent experiments. (B) Immunoblots for IRF4 in BACH2^KO or BACH2^Con cells with GAPDH as a loading control. (C) CD138 levels in BACH2^KO or BACH2^Con MCL cells were measured using FACS analysis (left), and the percentage of CD138⁺ cells in each group is indicated in the diagram (data are from 2 independent experiments) (right). **P < .01 (vs control cells; Student t test). (D) Under hypoxic stress, stabilized HIF-1α protein and increased heme synthesis are responsible for the decreased BACH2 levels at both the transcriptional and protein levels, thereby promoting MCL survival and progression in hypoxic microenvironments. BACH2 in turn modulates HIF-1α stability by downregulating PHD3 under normoxic conditions, indicating a fine-tuned interconnected loop between BACH2 and HIF-1α in MCL.