title: Targeting the microenvironment in chronic lymphocytic leukemia is changing the therapeutic landscape.
abstract: OBJECTIVE
  Despite ongoing efforts to decipher the cancer genome, discoveries of new targetable genetic lesions within cancer cells are rare. Therefore, alternative approaches are needed. Signals from the microenvironment are increasingly recognized as drivers of disease progression in hematologic and solid cancers. Consequently, there is growing interest in targeting the tumor-microenvironment cross-talk. This review highlights recent therapeutic advances in targeting the microenvironment in chronic lymphocytic leukemia (CLL).
  
  
  RESULTS
  CLL is the poster child for microenvironment-dependent malignancies, because the clonal CLL B cells are highly dependent on external signals for maintenance and expansion. These pathways recapitulate those responsible for normal B-cell expansion in germinal centers. The most prominent, conserved mechanism is B-cell receptor (BCR) signaling, which promotes CLL cell survival and expansion in lymphatic tissue areas designated proliferation centers. BCR signaling now can be targeted by new targeted kinase inhibitors.
  
  
  CONCLUSIONS
  Small molecule inhibitors of BCR signaling kinases, Bruton's tyrosine kinase (Btk) inhibitor ibrutinib and the phosphoinositide 3'-kinase delta (PI3Kδ) inhibitor GS-1101, are currently transforming the landscape of CLL therapy. This development exemplifies that the microenvironment has become a lively successful area of translational research.
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas 77230-1402, USA. jaburger@mdanderson.org
authors.forename: Jan A
authors.initials: JA
authors.lastname: Burger
mesh_terms: D000077329:Agammaglobulinaemia Tyrosine Kinase; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001402:B-Lymphocytes / Q000201:enzymology / Q000378:metabolism; D054377:Chemokine CXCL12 / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D058990:Molecular Targeted Therapy; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000378:metabolism; D015398:Signal Transduction; D000072377:Syk Kinase; D059016:Tumor Microenvironment / Q000187:drug effects*
chemical_list: D000077329:Agammaglobulinaemia Tyrosine Kinase; D000970:Antineoplastic Agents; D054377:Chemokine CXCL12; D047908:Intracellular Signaling Peptides and Proteins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; D011947:Receptors, Antigen, B-Cell; D019718:Receptors, CXCR4; D000072377:Syk Kinase; C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; C000625949:BTK protein, human; C000606896:SYK protein, human