title: Rational combination therapies targeting survival signaling in aggressive B-cell leukemia/lymphoma.
abstract: OBJECTIVE
  The identification of oncogenic 'driver' mutations and activated survival pathways in selected aggressive B-cell malignancies directs the development of novel adjunctive therapies using targeted small molecule inhibitors. With a focus on diffuse large B-cell lymphoma 'not otherwise specified', Hodgkin lymphoma and childhood B-cell precursor acute lymphoblastic leukemia, this review will provide an up-to-date account of the current literature on the development of new molecularly targeted treatment modalities for aggressive B-cell malignancies.
  
  
  RESULTS
  Subclassification of B-cell malignancies depending on their particular genetic 'driver' lesions and transcriptional and/or signaling signatures has led to the development of targeted therapeutic approaches using small molecule inhibitors to amend current combination chemotherapy.
  
  
  CONCLUSIONS
  Treatment outcome with current combination chemotherapy is still poor for subsets of aggressive B-cell malignancies, and demands development of targeted therapeutic approaches. Advanced gene expression profiling and genomic sequencing have revealed a more detailed landscape of recurrent alterations, allowing a better subclassification of B-cell lymphomas and leukemias. Many alterations directly or indirectly lead to activation of survival signaling pathways and expression of key oncoproteins and prosurvival molecules, including Janus kinase-signal transducer and activator of transcription (JAK-STAT), phosphatidylinositol-3 kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR), avian myelocytomatosis viral oncogene homolog (MYC) and B-cell lymphoma 2 (BCLl-2). Small molecule inhibitors targeting these proteins and pathways are currently being tested in clinical trials and preclinically to improve chemotherapeutic regimes and treatment outcomes.
authors.affiliation: aCancer Therapeutics Program, Gene Regulation Laboratory, The Peter MacCallum Cancer Centre, Melbourne bMonash Haematology, Monash Medical Centre cSouthern Clinical School, Monash University, Faculty of Medicine, Dentistry and Health Sciences, Clayton dSir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Michaela
authors.initials: M
authors.lastname: Waibel
authors.forename: Gareth
authors.initials: G
authors.lastname: Gregory
authors.forename: Jake
authors.initials: J
authors.lastname: Shortt
authors.forename: Ricky W
authors.initials: RW
authors.lastname: Johnstone
mesh_terms: D000818:Animals; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D015448:Leukemia, B-Cell / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*; D016393:Lymphoma, B-Cell / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*; D058990:Molecular Targeted Therapy; D015398:Signal Transduction / Q000187:drug effects