LAUSR

Signaling through the B‐cell receptor (BCR) has emerged as a potential key mechanism in CLL pathogenesis. It has been suggested that the BCR may induce antigen‐independent cell‐autonomous signaling in CLL. The importance of BCR signaling for CLL pathogenesis is underscored by the prognostic value of the IGVH mutational status or the restricted repertoire of IGVH gene usage (stereotypy). In addition, the use of whole exome sequencing and large, annotated clinical CLL databases has allowed describing the genomic landscape in CLL. Recurrent mutational patterns suggest that BCR and inflammatory pathways, NOTCH signaling, Wnt signaling, DNA damage control, chromatin modification, and RNA and ribosomal processing are frequently altered in CLL. In addition, the interaction of CLL cells with their microenvironment is essential for CLL pathogenesis. In knock‐ out models, leukemia‐associated macrophages were shown to be important components of the microenvironment of CLL cells. Even conventional therapeutics such as chemotherapy with alkylators and monoclonal antibodies mediate their effects trough compartment‐ restricted interactions with macrophages. Finally, agents supposed to exclusively target BCR‐associated kinases such as Lyn or Bruton tyrosine kinase seem to exert essential effects through the modulation of the leukemic microenvironment, since targeted deletions of these kinases reduce the capacity of macrophages to “feed” CLL growth. These insights have allowed to create a strongly improved understanding of the pathogenesis of this leukemia and to establish new, less toxic principles of therapies by using kinase inhibitors or Bcl2 antagonists.