title: Patient-derived xenotransplants can recapitulate the genetic driver landscape of acute leukemias.
abstract: Genomic studies have identified recurrent somatic mutations in acute leukemias. However, current murine models do not sufficiently encompass the genomic complexity of human leukemias. To develop preclinical models, we transplanted 160 samples from patients with acute leukemia (acute myeloid leukemia, mixed lineage leukemia, B-cell acute lymphoblastic leukemia, T-cell ALL) into immunodeficient mice. Of these, 119 engrafted with expected immunophenotype. Targeted sequencing of 374 genes and 265 frequently rearranged RNAs detected recurrent and novel genetic lesions in 48 paired primary tumor (PT) and patient-derived xenotransplant (PDX) samples. Overall, the frequencies of 274 somatic variant alleles correlated between PT and PDX samples, although the data were highly variable for variant alleles present at 0-10%. Seventeen percent of variant alleles were detected in either PT or PDX samples only. Based on variant allele frequency changes, 24 PT-PDX pairs were classified as concordant while the other 24 pairs showed various degree of clonal discordance. There was no correlation of clonal concordance with clinical parameters of diseases. Significantly more bone marrow samples than peripheral blood samples engrafted discordantly. These data demonstrate the utility of developing PDX banks for modeling human leukemia, and emphasize the importance of genomic profiling of PDX and patient samples to ensure concordance before performing mechanistic or therapeutic studies.
authors.affiliation: Foundation Medicine, Cambridge, MA, USA.
authors.forename: K
authors.initials: K
authors.lastname: Wang
authors.affiliation: Institute for Cancer Genetics Columbia University, New York, NY, USA.
authors.forename: M
authors.initials: M
authors.lastname: Sanchez-Martin
authors.affiliation: Center for Epigenetic Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: X
authors.initials: X
authors.lastname: Wang
authors.affiliation: Center for Epigenetic Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: K M
authors.initials: KM
authors.lastname: Knapp
authors.affiliation: Center for Epigenetic Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: R
authors.initials: R
authors.lastname: Koche
authors.affiliation: Center for Epigenetic Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: L
authors.initials: L
authors.lastname: Vu
authors.affiliation: Foundation Medicine, Cambridge, MA, USA.
authors.forename: M K
authors.initials: MK
authors.lastname: Nahas
authors.affiliation: Foundation Medicine, Cambridge, MA, USA.
authors.forename: J
authors.initials: J
authors.lastname: He
authors.affiliation: Foundation Medicine, Cambridge, MA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Hadler
authors.affiliation: Center for Epigenetic Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: E M
authors.initials: EM
authors.lastname: Stein
authors.affiliation: Center for Epigenetic Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: M S
authors.initials: MS
authors.lastname: Tallman
authors.affiliation: Foundation Medicine, Cambridge, MA, USA.
authors.forename: A L
authors.initials: AL
authors.lastname: Donahue
authors.affiliation: Foundation Medicine, Cambridge, MA, USA.
authors.forename: G M
authors.initials: GM
authors.lastname: Frampton
authors.affiliation: Foundation Medicine, Cambridge, MA, USA.
authors.forename: D
authors.initials: D
authors.lastname: Lipson
authors.affiliation: Foundation Medicine, Cambridge, MA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Roels
authors.affiliation: Foundation Medicine, Cambridge, MA, USA.
authors.forename: P J
authors.initials: PJ
authors.lastname: Stephens
authors.affiliation: Foundation Medicine, Cambridge, MA, USA.
authors.forename: E M
authors.initials: EM
authors.lastname: Sanford
authors.affiliation: Foundation Medicine, Cambridge, MA, USA.
authors.forename: T
authors.initials: T
authors.lastname: Brennan
authors.affiliation: Foundation Medicine, Cambridge, MA, USA.
authors.forename: G A
authors.initials: GA
authors.lastname: Otto
authors.affiliation: Foundation Medicine, Cambridge, MA, USA.
authors.forename: R
authors.initials: R
authors.lastname: Yelensky
authors.affiliation: Foundation Medicine, Cambridge, MA, USA.
authors.forename: V A
authors.initials: VA
authors.lastname: Miller
authors.affiliation: Center for Epigenetic Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: M G
authors.initials: MG
authors.lastname: Kharas
authors.affiliation: Center for Epigenetic Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: R L
authors.initials: RL
authors.lastname: Levine
authors.affiliation: Institute for Cancer Genetics Columbia University, New York, NY, USA.
authors.forename: A
authors.initials: A
authors.lastname: Ferrando
authors.affiliation: Center for Epigenetic Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: S A
authors.initials: SA
authors.lastname: Armstrong
authors.affiliation: Center for Epigenetic Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: A V
authors.initials: AV
authors.lastname: Krivtsov
mesh_terms: D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000818:Animals; D001773:Blood Cells / Q000637:transplantation; D016026:Bone Marrow Transplantation; D002417:Cattle; D002648:Child; D020869:Gene Expression Profiling; D064593:Heterografts / Q000473:pathology*; D006801:Humans; D016130:Immunophenotyping; D007938:Leukemia / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008875:Middle Aged; D055815:Young Adult