title: Genomics of chronic neutrophilic leukemia.
abstract: Chronic neutrophilic leukemia (CNL) is a distinct myeloproliferative neoplasm with a high prevalence (>80%) of mutations in the colony-stimulating factor 3 receptor (CSF3R). These mutations activate the receptor, leading to the proliferation of neutrophils that are a hallmark of CNL. Recently, the World Health Organization guidelines have been updated to includeCSF3Rmutations as part of the diagnostic criteria for CNL. Because of the high prevalence ofCSF3Rmutations in CNL, it is tempting to think of this disease as being solely driven by this genetic lesion. However, recent additional genomic characterization demonstrates that CNL has much in common with other chronic myeloid malignancies at the genetic level, such as the clinically related diagnosis atypical chronic myeloid leukemia. These commonalities include mutations inSETBP1, spliceosome proteins (SRSF2,U2AF1), and epigenetic modifiers (TET2,ASXL1). Some of these same mutations also have been characterized as frequent events in clonal hematopoiesis of indeterminate potential, suggesting a more complex disease evolution than was previously understood and raising the possibility that an age-related clonal process of preleukemic cells could precede the development of CNL. The order of acquisition ofCSF3Rmutations relative to mutations inSETBP1, epigenetic modifiers, or the spliceosome has been determined only in isolated case reports; thus, further work is needed to understand the impact of mutation chronology on the clonal evolution and progression of CNL. Understanding the complete landscape and chronology of genomic events in CNL will help in the development of improved therapeutic strategies for this patient population.
authors.affiliation: Division of Hematology and Medical Oncology.|Knight Cancer Institute, and.
authors.forename: Julia E
authors.initials: JE
authors.lastname: Maxson
authors.affiliation: Knight Cancer Institute, and.|Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University, Portland, OR.
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Tyner
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D060965:Clonal Evolution; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D049308:Dioxygenases; D018450:Disease Progression; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects*; D023281:Genomics; D006801:Humans; D054438:Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015467:Leukemia, Neutrophilic, Chronic / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D017410:Practice Guidelines as Topic; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D016184:Receptors, Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D000068103:Serine-Arginine Splicing Factors / Q000235:genetics / Q000378:metabolism; D000072668:Splicing Factor U2AF / Q000235:genetics / Q000378:metabolism
chemical_list: C473949:ASXL1 protein, human; D000970:Antineoplastic Agents; C517047:CSF3R protein, human; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D016184:Receptors, Colony-Stimulating Factor; D012097:Repressor Proteins; C425066:SETBP1 protein, human; D000072668:Splicing Factor U2AF; C076753:U2AF1 protein, human; C073288:SRSF2 protein, human; D000068103:Serine-Arginine Splicing Factors; D049308:Dioxygenases; C541081:TET2 protein, human