Casein kinase 1: a new tale of chronic lymphocytic leukemia (CLL) microenvironment

The biological history of chronic lymphocytic leukemia (CLL) is strictly related to the ability of leukemic cells to invade and manipulate tissue microenvironments. This evidence is unequivocal by the observation that despite an apparent long life in vivo, CLL cells undergo in spontaneous apoptosis in vitro during culture in complete medium (1). This can be avoided by culturing CLL cells in presence of a feeder layer represented by stromal cells (2), endothelial cells (3) and macrophage population (also called nurse-like cells) (4). In this perspective, CLL cells recirculate from blood to tissues through transient interactions with endothelium through firm adhesion molecules and chemokines that trigger integrin activation, thus inducing firm adhesion and transendothelial migration into tissues where stromal cells guide lymphocyte homing retention (5). CLL cells infiltrate bone marrow and lymph node compartments, disrupting the physiological architecture of tissues and generating hallmark structures called proliferation centers (6). Inside tissue microenvironments, CLL cells establish a complex crosstalk with surrounding non-transformed cells of stromal and immune compartments manipulating its biological functions. This crosstalk protects CLL cells from spontaneous or drug-induced apoptosis contributing to genetic instability and establishing a protective niche hiding residual CLL cells from conventional drugs (7). In the last years, novel kinase inhibitors of B-cell receptor signaling pathway (BCRi) have been approved for the treatment of CLL patients. These drugs, as ibrutinib and idelalisib, cause rapid resolution of lymphadenopathy and/or organomegaly with redistribution of leukemic cells from tissues into the blood (8)