title: Rapid expansion of preexisting nonleukemic hematopoietic clones frequently follows induction therapy for de novo AML.
abstract: There is interest in using leukemia-gene panels and next-generation sequencing to assess acute myelogenous leukemia (AML) response to induction chemotherapy. Studies have shown that patients with AML in morphologic remission may continue to have clonal hematopoiesis with populations closely related to the founding AML clone and that this confers an increased risk of relapse. However, it remains unknown how induction chemotherapy influences the clonal evolution of a patient's nonleukemic hematopoietic population. Here, we report that 5 of 15 patients with genetic clearance of their founding AML clone after induction chemotherapy had a concomitant expansion of a hematopoietic population unrelated to the initial AML. These populations frequently harbored somatic mutations in genes recurrently mutated in AML or myelodysplastic syndromes and were detectable at very low frequencies at the time of AML diagnosis. These results suggest that nonleukemic hematopoietic stem and progenitor cells, harboring specific aging-acquired mutations, may have a competitive fitness advantage after induction chemotherapy, expand, and persist long after the completion of chemotherapy. Although the clinical importance of these "rising" clones remains to be determined, it will be important to distinguish them from leukemia-related populations when assessing for molecular responses to induction chemotherapy.
authors.affiliation: Division of Oncology.
authors.forename: Terrence N
authors.identifier: http://orcid.org/0000-0001-5141-0745
authors.initials: TN
authors.lastname: Wong
authors.affiliation: McDonnell Genome Institute, and Division of Genomics and Bioinformatics, Washington University School of Medicine, St. Louis, MO;
authors.forename: Christopher A
authors.identifier: http://orcid.org/0000-0003-4266-6700
authors.initials: CA
authors.lastname: Miller
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN;
authors.forename: Jeffery M
authors.initials: JM
authors.lastname: Klco
authors.affiliation: McDonnell Genome Institute, and Division of Genomics and Bioinformatics, Washington University School of Medicine, St. Louis, MO;
authors.forename: Allegra
authors.initials: A
authors.lastname: Petti
authors.affiliation: McDonnell Genome Institute, and.
authors.forename: Ryan
authors.initials: R
authors.lastname: Demeter
authors.affiliation: Division of Oncology.
authors.forename: Nichole M
authors.initials: NM
authors.lastname: Helton
authors.affiliation: McDonnell Genome Institute, and.
authors.forename: Tiandao
authors.identifier: http://orcid.org/0000-0003-1650-0555
authors.initials: T
authors.lastname: Li
authors.affiliation: McDonnell Genome Institute, and.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Fulton
authors.affiliation: Division of Oncology.
authors.forename: Sharon E
authors.initials: SE
authors.lastname: Heath
authors.affiliation: McDonnell Genome Institute, and Siteman Cancer Center, Washington University, St. Louis, MO; and.
authors.forename: Elaine R
authors.identifier: http://orcid.org/0000-0002-5892-1553
authors.initials: ER
authors.lastname: Mardis
authors.affiliation: Division of Oncology, Siteman Cancer Center, Washington University, St. Louis, MO; and.
authors.forename: Peter
authors.initials: P
authors.lastname: Westervelt
authors.affiliation: Division of Oncology, Siteman Cancer Center, Washington University, St. Louis, MO; and.
authors.forename: John F
authors.initials: JF
authors.lastname: DiPersio
authors.affiliation: Division of Oncology, Siteman Cancer Center, Washington University, St. Louis, MO; and.
authors.forename: Matthew J
authors.identifier: http://orcid.org/0000-0002-7753-1091
authors.initials: MJ
authors.lastname: Walter
authors.affiliation: Division of Oncology, Siteman Cancer Center, Washington University, St. Louis, MO; and.
authors.forename: John S
authors.initials: JS
authors.lastname: Welch
authors.affiliation: Massachusetts General Hospital, Boston, MA.
authors.forename: Timothy A
authors.identifier: http://orcid.org/0000-0002-7710-1171
authors.initials: TA
authors.lastname: Graubert
authors.affiliation: McDonnell Genome Institute, and Siteman Cancer Center, Washington University, St. Louis, MO; and.
authors.forename: Richard K
authors.initials: RK
authors.lastname: Wilson
authors.affiliation: Division of Oncology, Siteman Cancer Center, Washington University, St. Louis, MO; and.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Ley
authors.affiliation: Division of Oncology, Siteman Cancer Center, Washington University, St. Louis, MO; and.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Link
mesh_terms: D000375:Aging / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D012008:Recurrence