title: Residual Disease in a Novel Xenograft Model of RUNX1-Mutated, Cytogenetically Normal Acute Myeloid Leukemia.
abstract: Cytogenetically normal acute myeloid leukemia (CN-AML) patients harboring RUNX1 mutations have a dismal prognosis with anthracycline/cytarabine-based chemotherapy. We aimed to develop an in vivo model of RUNX1-mutated, CN-AML in which the nature of residual disease in this molecular disease subset could be explored. We utilized a well-characterized patient-derived, RUNX1-mutated CN-AML line (CG-SH). Tail vein injection of CG-SH into NOD scid gamma mice led to leukemic engraftment in the bone marrow, spleen, and peripheral blood within 6 weeks. Treatment of leukemic mice with anthracycline/cytarabine-based chemotherapy resulted in clearance of disease from the spleen and peripheral blood, but persistence of disease in the bone marrow as assessed by flow cytometry and secondary transplantation. Whole exome sequencing of CG-SH revealed mutations in ASXL1, CEBPA, GATA2, and SETBP1, not previously reported. We conclude that CG-SH xenografts are a robust, reproducible in vivo model of CN-AML in which to explore mechanisms of chemotherapy resistance and novel therapeutic approaches.
authors.affiliation: Department of Medicine, James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York, United States of America.
authors.forename: Umayal
authors.initials: U
authors.lastname: Sivagnanalingam
authors.affiliation: Department of Medicine, James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York, United States of America.
authors.forename: Marlene
authors.initials: M
authors.lastname: Balys
authors.affiliation: Department of Medicine, James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York, United States of America.
authors.forename: Allison
authors.initials: A
authors.lastname: Eberhardt
authors.affiliation: Department of Pathology & Laboratory Medicine, University of Rochester Medical Center, Rochester, New York, United States of America.
authors.forename: Nancy
authors.initials: N
authors.lastname: Wang
authors.affiliation: Genomics Research Center, University of Rochester Medical Center, Rochester, New York, United States of America.
authors.forename: Jason R
authors.initials: JR
authors.lastname: Myers
authors.affiliation: Genomics Research Center, University of Rochester Medical Center, Rochester, New York, United States of America; Department of Microbiology & Immunology, James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York, United States of America.
authors.forename: John M
authors.initials: JM
authors.lastname: Ashton
authors.affiliation: Department of Medicine, James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York, United States of America.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Becker
authors.affiliation: Department of Medicine, James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York, United States of America.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Calvi
authors.affiliation: Department of Medicine, James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York, United States of America.
authors.forename: Jason H
authors.initials: JH
authors.lastname: Mendler
mesh_terms: D000818:Animals; D018943:Anthracyclines / Q000494:pharmacology / Q000627:therapeutic use; D001853:Bone Marrow / Q000473:pathology; D045744:Cell Line, Tumor; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics*; D003561:Cytarabine / Q000494:pharmacology / Q000627:therapeutic use; D020732:Cytogenetic Analysis; D004252:DNA Mutational Analysis; D059472:Exome / Q000235:genetics; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009154:Mutation / Q000235:genetics*; D018365:Neoplasm, Residual / Q000235:genetics* / Q000473:pathology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D018943:Anthracyclines; D050676:Core Binding Factor Alpha 2 Subunit; D003561:Cytarabine