title: Colony-Stimulating Factor-1 Receptor Is Required for Nurse-like Cell Survival in Chronic Lymphocytic Leukemia.
abstract: OBJECTIVE
  Monocytes and their progeny are abundant constituents of the tumor microenvironment in lymphoproliferative disorders, including chronic lymphocytic leukemia (CLL). Monocyte-derived cells, including nurse-like cells (NLC) in CLL, promote lymphocyte proliferation and survival, confer resistance to chemotherapy, and are associated with more rapid disease progression. Colony-stimulating factor-1 receptor (CSF-1R) regulates the homeostatic survival of tissue-resident macrophages. Therefore, we sought to determine whether CSF-1R is similarly required for NLC survival.
  
  
  METHODS
  CSF-1R expression by NLC was examined by flow cytometry and IHC. CSF-1R blocking studies were performed using an antagonistic mAb to examine its role in NLC generation and in CLL survival. A rational search strategy was performed to identify a novel tyrosine kinase inhibitor (TKI) targeting CSF-1R. The influence of TKI-mediated CSF-1R inhibition on NLC and CLL viability was examined.
  
  
  RESULTS
  We demonstrated that the generation and survival of NLC in CLL is dependent upon CSF-1R signaling. CSF-1R blockade is associated with significant depletion of NLC and consequently inhibits CLL B-cell survival. We found that the JAK2/FLT3 inhibitor pacritinib suppresses CSF-1R signaling, thereby preventing the generation and survival of NLC and impairs CLL B-cell viability.
  
  
  CONCLUSIONS
  CSF-1R is a novel therapeutic target that may be exploited in lymphoproliferative disorders, like CLL, that are dependent upon lymphoma-associated macrophages. Clin Cancer Res; 22(24); 6118-28. ©2016 AACR.
authors.affiliation: Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Avery
authors.initials: A
authors.lastname: Polk
authors.affiliation: Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Ye
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Tianjiao
authors.initials: T
authors.lastname: Wang
authors.affiliation: Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Erlene
authors.initials: E
authors.lastname: Seymour
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Nathanael G
authors.initials: NG
authors.lastname: Bailey
authors.affiliation: CTI Biopharma, Seattle, Washington.
authors.forename: Jack W
authors.initials: JW
authors.lastname: Singer
authors.affiliation: Department of Biostatistics, University of Michigan, Ann Arbor, Michigan.
authors.forename: Philip S
authors.initials: PS
authors.lastname: Boonstra
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Megan S
authors.initials: MS
authors.lastname: Lim
authors.affiliation: Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Sami
authors.initials: S
authors.lastname: Malek
authors.affiliation: Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, Ann Arbor, Michigan. rywilcox@med.umich.edu.
authors.forename: Ryan A
authors.initials: RA
authors.lastname: Wilcox
mesh_terms: D001402:B-Lymphocytes / Q000187:drug effects / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D016186:Receptor, Macrophage Colony-Stimulating Factor
chemical_list: D047428:Protein Kinase Inhibitors; D020794:Receptor Protein-Tyrosine Kinases; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; C000622186:CSF1R protein, human; D016186:Receptor, Macrophage Colony-Stimulating Factor