title: Do mantle cell lymphomas have an 'Achilles heel'?
abstract: OBJECTIVE
  Mantle cell lymphoma (MCL) is a mature B-cell malignancy that continues to have a high mortality rate. In this article, we discuss key pathogenic pathways in MCL biology and their possible therapeutic targeting.
  
  
  RESULTS
  In addition to cyclin-D1, the transcription factor SOX-11 emerged as a common characteristic of MCL. Genomic studies have identified a number of recurrently mutated genes; in order of descending frequency these include ATM, CCND1, UBR5, TP53, BIRC3, NOTCH1/2 and TRAF2. However, no clear oncogenic driver has been identified. In contrast, several observations indicate that MCL cells are antigen-experienced cells and that the tumor microenvironment and B-cell receptor engagement are important. This is underscored by the impressive clinical responses achieved with the Bruton's tyrosine kinase inhibitor ibrutinib. Recently identified activating mutations in the noncanonical nuclear factor-kappa B pathway could give rise to ibrutinib resistance. Poly-ADP ribose polymerase and aurora kinase inhibitors may be synthetic lethal with the common aberrations in DNA damage pathways found in MCL. Also, ABT-199, a potent and selective inhibitor of B-cell lymphoma 2, has promising activity in early studies.
  
  
  CONCLUSIONS
  MCL is a heterogeneous disease, and no single Achilles heel has been identified. Nevertheless, genomic, molecular and clinical studies have revealed vulnerabilities that can be exploited for effective therapy.
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Nakhle
authors.initials: N
authors.lastname: Saba
authors.forename: Adrian
authors.initials: A
authors.lastname: Wiestner
mesh_terms: D019938:Cyclin D1 / Q000378:metabolism; D004249:DNA Damage; D006801:Humans; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism*; D058990:Molecular Targeted Therapy; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D059016:Tumor Microenvironment
chemical_list: D019253:Proto-Oncogene Proteins c-bcl-2; D019938:Cyclin D1