title: Comprehensive genomic analysis reveals FLT3 activation and a therapeutic strategy for a patient with relapsed adult B-lymphoblastic leukemia.
abstract: The genomic events responsible for the pathogenesis of relapsed adult B-lymphoblastic leukemia (B-ALL) are not yet clear. We performed integrative analysis of whole-genome, whole-exome, custom capture, whole-transcriptome (RNA-seq), and locus-specific genomic assays across nine time points from a patient with primary de novo B-ALL. Comprehensive genome and transcriptome characterization revealed a dramatic tumor evolution during progression, yielding a tumor with complex clonal architecture at second relapse. We observed and validated point mutations in EP300 and NF1, a highly expressed EP300-ZNF384 gene fusion, a microdeletion in IKZF1, a focal deletion affecting SETD2, and large deletions affecting RB1, PAX5, NF1, and ETV6. Although the genome analysis revealed events of potential biological relevance, no clinically actionable treatment options were evident at the time of the second relapse. However, transcriptome analysis identified aberrant overexpression of the targetable protein kinase encoded by the FLT3 gene. Although the patient had refractory disease after salvage therapy for the second relapse, treatment with the FLT3 inhibitor sunitinib rapidly induced a near complete molecular response, permitting the patient to proceed to a matched-unrelated donor stem cell transplantation. The patient remains in complete remission more than 4 years later. Analysis of this patient's relapse genome revealed an unexpected, actionable therapeutic target that led to a specific therapy associated with a rapid clinical response. For some patients with relapsed or refractory cancers, this approach may indicate a novel therapeutic intervention that could alter outcome.
authors.affiliation: McDonnell Genome Institute, Washington University, St. Louis, MO, USA; Department of Genetics, Washington University, St. Louis, MO, USA; Siteman Cancer Center, Washington University, St. Louis, MO, USA. Electronic address: mgriffit@wustl.edu.
authors.forename: Malachi
authors.initials: M
authors.lastname: Griffith
authors.affiliation: McDonnell Genome Institute, Washington University, St. Louis, MO, USA; Department of Genetics, Washington University, St. Louis, MO, USA; Siteman Cancer Center, Washington University, St. Louis, MO, USA; Department of Medicine, Washington University, St. Louis, MO, USA.
authors.forename: Obi L
authors.initials: OL
authors.lastname: Griffith
authors.affiliation: McDonnell Genome Institute, Washington University, St. Louis, MO, USA.
authors.forename: Kilannin
authors.initials: K
authors.lastname: Krysiak
authors.affiliation: McDonnell Genome Institute, Washington University, St. Louis, MO, USA.
authors.forename: Zachary L
authors.initials: ZL
authors.lastname: Skidmore
authors.affiliation: Department of Medicine, Washington University, St. Louis, MO, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Christopher
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Jeffery M
authors.initials: JM
authors.lastname: Klco
authors.affiliation: McDonnell Genome Institute, Washington University, St. Louis, MO, USA.
authors.forename: Avinash
authors.initials: A
authors.lastname: Ramu
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Tamara L
authors.initials: TL
authors.lastname: Lamprecht
authors.affiliation: McDonnell Genome Institute, Washington University, St. Louis, MO, USA.
authors.forename: Alex H
authors.initials: AH
authors.lastname: Wagner
authors.affiliation: McDonnell Genome Institute, Washington University, St. Louis, MO, USA.
authors.forename: Katie M
authors.initials: KM
authors.lastname: Campbell
authors.affiliation: McDonnell Genome Institute, Washington University, St. Louis, MO, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Lesurf
authors.affiliation: McDonnell Genome Institute, Washington University, St. Louis, MO, USA.
authors.forename: Jasreet
authors.initials: J
authors.lastname: Hundal
authors.affiliation: McDonnell Genome Institute, Washington University, St. Louis, MO, USA.
authors.forename: Jin
authors.initials: J
authors.lastname: Zhang
authors.affiliation: McDonnell Genome Institute, Washington University, St. Louis, MO, USA.
authors.forename: Nicholas C
authors.initials: NC
authors.lastname: Spies
authors.affiliation: McDonnell Genome Institute, Washington University, St. Louis, MO, USA; Siteman Cancer Center, Washington University, St. Louis, MO, USA.
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Ainscough
authors.affiliation: McDonnell Genome Institute, Washington University, St. Louis, MO, USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Larson
authors.affiliation: Department of Medicine, Washington University, St. Louis, MO, USA.
authors.forename: Sharon E
authors.initials: SE
authors.lastname: Heath
authors.affiliation: McDonnell Genome Institute, Washington University, St. Louis, MO, USA.
authors.forename: Catrina
authors.initials: C
authors.lastname: Fronick
authors.affiliation: McDonnell Genome Institute, Washington University, St. Louis, MO, USA.
authors.forename: Shelly
authors.initials: S
authors.lastname: O'Laughlin
authors.affiliation: McDonnell Genome Institute, Washington University, St. Louis, MO, USA.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Fulton
authors.affiliation: McDonnell Genome Institute, Washington University, St. Louis, MO, USA.
authors.forename: Vincent
authors.initials: V
authors.lastname: Magrini
authors.affiliation: McDonnell Genome Institute, Washington University, St. Louis, MO, USA.
authors.forename: Sean
authors.initials: S
authors.lastname: McGrath
authors.affiliation: McDonnell Genome Institute, Washington University, St. Louis, MO, USA.
authors.forename: Scott M
authors.initials: SM
authors.lastname: Smith
authors.affiliation: McDonnell Genome Institute, Washington University, St. Louis, MO, USA; Department of Medicine, Washington University, St. Louis, MO, USA.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Miller
authors.affiliation: McDonnell Genome Institute, Washington University, St. Louis, MO, USA; Siteman Cancer Center, Washington University, St. Louis, MO, USA; Department of Medicine, Washington University, St. Louis, MO, USA; Department of Biomedical Engineering, Washington University, St. Louis, MO, USA.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Maher
authors.affiliation: Siteman Cancer Center, Washington University, St. Louis, MO, USA; Department of Medicine, Washington University, St. Louis, MO, USA; Department of Pathology, Washington University, St. Louis, MO, USA.
authors.forename: Jacqueline E
authors.initials: JE
authors.lastname: Payton
authors.affiliation: McDonnell Genome Institute, Washington University, St. Louis, MO, USA.
authors.forename: Jason R
authors.initials: JR
authors.lastname: Walker
authors.affiliation: McDonnell Genome Institute, Washington University, St. Louis, MO, USA.
authors.forename: James M
authors.initials: JM
authors.lastname: Eldred
authors.affiliation: Siteman Cancer Center, Washington University, St. Louis, MO, USA; Department of Medicine, Washington University, St. Louis, MO, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Walter
authors.affiliation: Siteman Cancer Center, Washington University, St. Louis, MO, USA; Department of Medicine, Washington University, St. Louis, MO, USA.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Link
authors.affiliation: Massachusetts General Hospital Cancer Center, Boston, MA, USA.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Graubert
authors.affiliation: Siteman Cancer Center, Washington University, St. Louis, MO, USA; Department of Medicine, Washington University, St. Louis, MO, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Westervelt
authors.affiliation: Department of Pathology, Washington University, St. Louis, MO, USA.
authors.forename: Shashikant
authors.initials: S
authors.lastname: Kulkarni
authors.affiliation: Siteman Cancer Center, Washington University, St. Louis, MO, USA; Department of Medicine, Washington University, St. Louis, MO, USA.
authors.forename: John F
authors.initials: JF
authors.lastname: DiPersio
authors.affiliation: McDonnell Genome Institute, Washington University, St. Louis, MO, USA; Department of Genetics, Washington University, St. Louis, MO, USA; Siteman Cancer Center, Washington University, St. Louis, MO, USA; Department of Medicine, Washington University, St. Louis, MO, USA.
authors.forename: Elaine R
authors.initials: ER
authors.lastname: Mardis
authors.affiliation: McDonnell Genome Institute, Washington University, St. Louis, MO, USA; Department of Genetics, Washington University, St. Louis, MO, USA; Siteman Cancer Center, Washington University, St. Louis, MO, USA; Department of Medicine, Washington University, St. Louis, MO, USA.
authors.forename: Richard K
authors.initials: RK
authors.lastname: Wilson
authors.affiliation: McDonnell Genome Institute, Washington University, St. Louis, MO, USA; Department of Genetics, Washington University, St. Louis, MO, USA; Siteman Cancer Center, Washington University, St. Louis, MO, USA; Department of Medicine, Washington University, St. Louis, MO, USA. Electronic address: timley@wustl.edu.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Ley
mesh_terms: D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001706:Biopsy; D001853:Bone Marrow / Q000473:pathology; D016026:Bone Marrow Transplantation; D003520:Cyclophosphamide / Q000627:therapeutic use; D020732:Cytogenetic Analysis; D003907:Dexamethasone / Q000627:therapeutic use; D004317:Doxorubicin / Q000627:therapeutic use; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D014644:Genetic Variation; D023281:Genomics / Q000379:methods; D006086:Graft vs Host Disease / Q000188:drug therapy / Q000209:etiology; D006801:Humans; D008297:Male; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000175:diagnosis / Q000235:genetics* / Q000628:therapy*; D012008:Recurrence; D015533:Transcriptional Activation; D014184:Transplantation, Homologous; D014750:Vincristine / Q000627:therapeutic use; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics*
chemical_list: D014750:Vincristine; D003907:Dexamethasone; D004317:Doxorubicin; D003520:Cyclophosphamide; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3