title: Coming full circle: 70 years of chronic lymphocytic leukemia cell redistribution, from glucocorticoids to inhibitors of B-cell receptor signaling.
abstract: Chronic lymphocytic leukemia (CLL) cells proliferate in pseudofollicles within the lymphatic tissues, where signals from the microenvironment and BCR signaling drive the expansion of the CLL clone. Mobilization of tissue-resident cells into the blood removes CLL cells from this nurturing milieu and sensitizes them to cytotoxic drugs. This concept recently gained momentum after the clinical activity of kinase inhibitors that target BCR signaling (spleen tyrosine kinase, Bruton tyrosine kinase, PI3Kδ inhibitors) was established. Besides antiproliferative activity, these drugs cause CLL cell redistribution with rapid lymph node shrinkage, along with a transient surge in lymphocytosis, before inducing objective remissions. Inactivation of critical CLL homing mechanism (chemokine receptors, adhesion molecules), thwarting tissue retention and recirculation into the tissues, appears to be the basis for this striking clinical activity. This effect of BCR-signaling inhibitors resembles redistribution of CLL cells after glucocorticoids, described as early as in the 1940s. As such, we are witnessing a renaissance of the concept of leukemia cell redistribution in modern CLL therapy. Here, we review the molecular basis of CLL cell trafficking, homing, and redistribution and similarities between old and new drugs affecting these processes. In addition, we outline how these discoveries are changing our understanding of CLL biology and therapy.
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77230, USA. jaburger@mdanderson.org
authors.forename: Jan A
authors.initials: JA
authors.lastname: Burger
authors.forename: Emili
authors.initials: E
authors.lastname: Montserrat
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D058492:Drug Repositioning; D005938:Glucocorticoids / Q000627:therapeutic use*; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy*; D008954:Models, Biological; D011947:Receptors, Antigen, B-Cell / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents; D005938:Glucocorticoids; D011947:Receptors, Antigen, B-Cell