title: Hematopoietic expression of oncogenic BRAF promotes aberrant growth of monocyte-lineage cells resistant to PLX4720.
abstract: Mutational activation of BRAF leading to expression of the BRAF(V600E) oncoprotein was recently identified in a high percentage of specific hematopoietic neoplasms in monocyte/histiocyte and mature B-cell lineages. Although BRAF(V600E) is a driver oncoprotein and pharmacologic target in solid tumors such as melanoma, lung, and thyroid cancer, it remains unknown whether BRAF(V600E) is an appropriate therapeutic target in hematopoietic neoplasms. To address this critical question, we generated a mouse model expressing inducible BRAF(V600E) in the hematopoietic system, and evaluated the efficacy of pathway-targeted therapeutics against primary hematopoietic cells. In this model, BRAF(V600E) expression conferred cytokine-independent growth to monocyte/macrophage-lineage progenitors leading to aberrant in vivo and in vitro monocyte/macrophage expansion. Furthermore, transplantation of BRAF(V600E)-expressing bone marrow cells promoted an in vivo pathology most notable for monocytosis in hematopoietic tissues and visceral organs. In vitro analysis revealed that MAP-ERK kinase inhibition, but not RAF inhibition, effectively suppressed cytokine-independent clonal growth of monocyte/macrophage-lineage progenitors. However, combined RAF and phosphoinositide 3-kinase (PI3K) inhibition effectively inhibited cytokine-independent colony formation, suggesting autocrine PI3K pathway activation. Taken together, these results provide evidence that constitutively activated BRAF(V600E) drives aberrant proliferation of monocyte-lineage cells.
  
  
  CONCLUSIONS
  This study supports the development of pathway-targeted therapeutics in the treatment of BRAF(V600E)-expressing hematopoietic neoplasms in the monocyte/histiocyte lineage.
authors.affiliation: Department of Laboratory Medicine, University of California, San Francisco, 513 Parnassus Ave, Room S-561, San Francisco, CA 94143-0100. leavitta@labmed2.ucsf.edu.
authors.forename: Tamihiro
authors.initials: T
authors.lastname: Kamata
authors.forename: David
authors.initials: D
authors.lastname: Dankort
authors.forename: Jing
authors.initials: J
authors.lastname: Kang
authors.forename: Susan
authors.initials: S
authors.lastname: Giblett
authors.forename: Catrin A
authors.initials: CA
authors.lastname: Pritchard
authors.forename: Martin
authors.initials: M
authors.lastname: McMahon
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Leavitt
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D016026:Bone Marrow Transplantation; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004159:Diphenylamine / Q000031:analogs & derivatives / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004920:Erythropoiesis; D005663:Furans / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D019337:Hematologic Neoplasms / Q000188:drug therapy / Q000473:pathology; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D055017:Monocyte-Macrophage Precursor Cells / Q000187:drug effects / Q000502:physiology*; D009000:Monocytes / Q000187:drug effects / Q000502:physiology*; D038042:Myelopoiesis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D015398:Signal Transduction; D013449:Sulfonamides / Q000494:pharmacology*; D048490:raf Kinases / Q000037:antagonists & inhibitors*
chemical_list: D001549:Benzamides; D016207:Cytokines; D005663:Furans; D007211:Indoles; C522973:PI103; C528407:PLX 4720; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011743:Pyrimidines; D013449:Sulfonamides; C506614:mirdametinib; D004159:Diphenylamine; D048493:Proto-Oncogene Proteins B-raf; D048490:raf Kinases