Assessment of drug sensitivity in hematopoietic stem and progenitor cells from acute myelogenous leukemia and myelodysplastic syndrome ex vivo

Katherine L.B. Knorr, Laura E. Finn, B. Douglas Smith, Allan D. Hess, James M. Foran, Judith E. Karp, Scott H. Kaufmann

Research output: Contribution to journalArticle

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 hourswith drug versus diluent. Wedemonstrate thatMLN4924 exerts a cytotoxic effect onMDS andAML stemand 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.

LanguageEnglish (US)
Pages840-850
Number of pages11
JournalStem Cells Translational Medicine
Volume6
Issue number3
DOIs
StatePublished - Mar 1 2017

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Myelodysplastic Syndromes
Hematopoietic Stem Cells
Acute Myeloid Leukemia
Myeloid Progenitor Cells
Stem Cells
Pharmaceutical Preparations
Cytarabine
Population
Megakaryocyte-Erythroid Progenitor Cells
Flow Cytometry
Bone Marrow
Granulocyte Precursor Cells
Enzyme Inhibitors
Standard of Care
Monocytes
Cell Count
Antibodies
Therapeutics
Neoplasms

Keywords

  • Acute myelogenous leukemia
  • Hematopoietic stem cells
  • MLN4924
  • Myelodysplastic syndrome
  • Myeloid progenitor cells

ASJC Scopus subject areas

  • Developmental Biology
  • Cell Biology

Cite this

Assessment of drug sensitivity in hematopoietic stem and progenitor cells from acute myelogenous leukemia and myelodysplastic syndrome ex vivo. / Knorr, Katherine L.B.; Finn, Laura E.; Douglas Smith, B.; Hess, Allan D.; Foran, James M.; Karp, Judith E.; Kaufmann, Scott H.

In: Stem Cells Translational Medicine, Vol. 6, No. 3, 01.03.2017, p. 840-850.

Research output: Contribution to journalArticle

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