Simplified schema of pre-BCR signaling and its inhibition by ibrutinib. (A) Pre-BCR assembles with Igα and Igβ to signal through spleen tyrosine kinase (SYK), BTK, phospholipase C-gamma2, SRC-homology-2-domain-containing leukocyte protein of 65 kDa (SLP65), and with SRC-family protein tyrosine kinases, such as LYN, to activate downstream pathways (AKT/ERK/mechanistic target of rapamycin [mTOR]), which promote cell proliferation. Ibrutinib interferes with pre-BCR signaling by inhibiting multiple targets, including BTK and B-lymphocyte kinase (BLK); impairs phosphorylation of the downstream effectors AKT/ERK/mTOR; and reduces BCL6 expression. (B) Schematic representation of bone marrow niche. Kim et al showed that ibrutinib inhibits chemotaxis of pre-B-ALL cells toward CXCL12. P, phosphorylation sites; PI3Kδ, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit δ. Professional illustration by Patrick Lane, ScEYEnce Studios.