FoxO1 signaling in B cell malignancies and its therapeutic targeting.

FoxO transcription factors (FoxO1, FoxO3a, FoxO4, FoxO6) are a highlyevolutionary conserved subfamily of the ‘forkhead’ box proteins. They havetraditionally been considered tumor suppressors, but FoxO1 also exhibitsoncogenic properties. The complex nature of FoxO1 is illustrated by its vari-ous roles in B cell development and differentiation, immunoglobulin gene rear-rangement and cell-surface B cell receptor (BCR) structure, DNA damagecontrol, cell cycle regulation, and germinal center reaction. FoxO1 is tightlyregulated at a transcriptional (STAT3, HEB, EBF, FoxOs) andpost-transcriptional level (Akt, AMPK, CDK2, GSK3, IKKs, JNK, MAP-K/Erk, SGK1, miRNA). In B cell malignancies, recurrent FoxO1 activatingmutations (S22/T24) and aberrant nuclear export and activity have beendescribed, underscoring the potential of its therapeutic inhibition. Here, wereview FoxO1’s roles across B cell and myeloid malignancies, namely acutelymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lym-phocytic leukemia (CLL), follicular lymphoma (FL), diffuse large B cell lym-phoma (DLBCL), mantle cell lymphoma (MCL), Burkitt lymphoma (BL),Hodgkin lymphoma (HL), and multiple myeloma (MM). We also discuss pre-clinical evidence for FoxO1 targeting by currently available inhibitors(AS1708727, AS1842856, cpd10).