title: Assessment of Drug Sensitivity in Hematopoietic Stem and Progenitor Cells from Acute Myelogenous Leukemia and Myelodysplastic Syndrome Ex Vivo.
abstract: Current understanding suggests that malignant stem and progenitor cells must be reduced or eliminated for prolonged remissions in myeloid neoplasms such as acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS). Multicolor flow cytometry has been widely used to distinguish stem and myeloid progenitor cells from other populations in normal and malignant bone marrow. In this study, we present a method for assessing drug sensitivity in MDS and AML patient hematopoietic stem and myeloid progenitor cell populations ex vivo using the investigational Nedd8-activating enzyme inhibitor MLN4924 and standard-of-care agent cytarabine as examples. Utilizing a multicolor flow cytometry antibody panel for identification of hematopoietic stem cells, multipotent progenitors, common myeloid progenitors, granulocyte-monocyte progenitors, and megakaryocyte-erythroid progenitors present in mononuclear cell fractions isolated from bone marrow aspirates, we compare stem and progenitor cell counts after treatment for 24 hours with drug versus diluent. We demonstrate that MLN4924 exerts a cytotoxic effect on MDS and AML stem and progenitor cell populations, whereas cytarabine has more limited effects. Further application of this method for evaluating drug effects on these populations ex vivo and in vivo may inform rational design and selection of therapies in the clinical setting. Stem Cells Translational Medicine 2017;6:840-850.
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Katherine L B
authors.initials: KL
authors.lastname: Knorr
authors.affiliation: Division of Hematology and Oncology, Mayo Clinic, Jacksonville, Florida, USA.
authors.forename: Laura E
authors.initials: LE
authors.lastname: Finn
authors.affiliation: Division of Oncology Research, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: B Douglas
authors.initials: BD
authors.lastname: Smith
authors.affiliation: Division of Oncology Research, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Allan D
authors.initials: AD
authors.lastname: Hess
authors.affiliation: Division of Hematology and Oncology, Mayo Clinic, Jacksonville, Florida, USA.
authors.forename: James M
authors.initials: JM
authors.lastname: Foran
authors.affiliation: Division of Oncology Research, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Judith E
authors.initials: JE
authors.lastname: Karp
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota, USA.|Division of Hematological Malignancies, Sidney Kimmel Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Scott H
authors.initials: SH
authors.lastname: Kaufmann
mesh_terms: D002452:Cell Count; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003517:Cyclopentanes / Q000494:pharmacology / Q000627:therapeutic use*; D003561:Cytarabine / Q000494:pharmacology; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000473:pathology*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000473:pathology*; D009190:Myelodysplastic Syndromes / Q000188:drug therapy* / Q000473:pathology*; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D003517:Cyclopentanes; D011743:Pyrimidines; D003561:Cytarabine; C539933:pevonedistat
keywords: Acute myelogenous leukemia; Hematopoietic stem cells; MLN4924; Myelodysplastic syndrome; Myeloid progenitor cells