title: Leukemic stem cell frequency: a strong biomarker for clinical outcome in acute myeloid leukemia.
abstract: BACKGROUND
  Treatment failure in acute myeloid leukemia is probably caused by the presence of leukemia initiating cells, also referred to as leukemic stem cells, at diagnosis and their persistence after therapy. Specific identification of leukemia stem cells and their discrimination from normal hematopoietic stem cells would greatly contribute to risk stratification and could predict possible relapses.
  
  
  RESULTS
  For identification of leukemic stem cells, we developed flow cytometric methods using leukemic stem cell associated markers and newly-defined (light scatter) aberrancies. The nature of the putative leukemic stem cells and normal hematopoietic stem cells, present in the same patient's bone marrow, was demonstrated in eight patients by the presence or absence of molecular aberrancies and/or leukemic engraftment in NOD-SCID IL-2Rγ-/- mice. At diagnosis (n=88), the frequency of the thus defined neoplastic part of CD34+CD38- putative stem cell compartment had a strong prognostic impact, while the neoplastic parts of the CD34+CD38+ and CD34- putative stem cell compartments had no prognostic impact at all. After different courses of therapy, higher percentages of neoplastic CD34+CD38- cells in complete remission strongly correlated with shorter patient survival (n=91). Moreover, combining neoplastic CD34+CD38- frequencies with frequencies of minimal residual disease cells (n=91), which reflect the total neoplastic burden, revealed four patient groups with different survival.
  
  
  CONCLUSIONS
  Discrimination between putative leukemia stem cells and normal hematopoietic stem cells in this large-scale study allowed to demonstrate the clinical importance of putative CD34+CD38- leukemia stem cells in AML. Moreover, it offers new opportunities for the development of therapies directed against leukemia stem cells, that would spare normal hematopoietic stem cells, and, moreover, enables in vivo and ex vivo screening for potential efficacy and toxicity of new therapies.
authors.affiliation: Department of Hematology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Monique
authors.initials: M
authors.lastname: Terwijn
authors.affiliation: Department of Hematology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Wendelien
authors.initials: W
authors.lastname: Zeijlemaker
authors.affiliation: Department of Hematology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Angèle
authors.initials: A
authors.lastname: Kelder
authors.affiliation: Department of Hematology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Arjo P
authors.initials: AP
authors.lastname: Rutten
authors.affiliation: Department of Hematology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Alexander N
authors.initials: AN
authors.lastname: Snel
authors.affiliation: Department of Hematology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Willemijn J
authors.initials: WJ
authors.lastname: Scholten
authors.affiliation: Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Pabst
authors.affiliation: Department of Hematology, University Hospital Leuven, Leuven, Belgium.
authors.forename: Gregor
authors.initials: G
authors.lastname: Verhoef
authors.affiliation: Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Bob
authors.initials: B
authors.lastname: Löwenberg
authors.affiliation: Department of Hematology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Sonja
authors.initials: S
authors.lastname: Zweegman
authors.affiliation: Department of Hematology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Gert J
authors.initials: GJ
authors.lastname: Ossenkoppele
authors.affiliation: Department of Hematology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Gerrit J
authors.initials: GJ
authors.lastname: Schuurhuis
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D015415:Biomarkers; D002452:Cell Count; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D016130:Immunophenotyping; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000175:diagnosis* / Q000378:metabolism / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D011379:Prognosis; D055815:Young Adult
chemical_list: D018952:Antigens, CD34; D015415:Biomarkers; D051997:ADP-ribosyl Cyclase 1