MARCKS modulates CLL cell signaling. MARCKS tethers PIP2 to the cell membrane and binds Ca2⁺/calmodulin and F-actin, thereby regulating cell motility and the function of the cytoskeleton. By hindering BCR clustering and capturing PIP2, thereby limiting availability of PIP2 for PI3K-related signaling, membranous MARCKS tones down signaling of the BCR and chemokine receptors. In this issue of Blood, Beckmann et al demonstrate that M-CLL patients have higher MARCKS levels, and UM-CLL patients have lower MARCKS levels. This differential MARCKS expression correlates with higher or lower capacity for BCR and chemokine receptor signaling, respectively. These preclinical findings are translated into the clinical situation in CLL patients treated with the BTK inhibitor acalabrutinib. Acalabrutinib, as seen with all BTK inhibitors, induces redistribution lymphocytosis due to the mobilization of lymph node–resident CLL cells into the peripheral blood. This redistribution lymphocytosis is more pronounced in patients with low MARCKS and UM-CLL (and high signaling activity/dependency) and less pronounced in patients with high MARCKS (lower signaling activity/dependency). The signaling modulation by MARCKS is further regulated by its activation/phosphorylation status; phosphorylation of MARCKS (eg, from enhanced BCR signaling) results in relocation of MARCKS from the membrane into the cytoplasm, thereby fostering BCR clustering and enhanced access to PIP2 and strengthening BCR- and migration-related signaling, preferentially in UM-CLL. BTKi, BTK inhibitor; Ig, immunoglobulin.