title: High stem cell frequency in acute myeloid leukemia at diagnosis predicts high minimal residual disease and poor survival.
abstract: OBJECTIVE
  In CD34-positive acute myeloid leukemia (AML), the leukemia-initiating event originates from the CD34(+)CD38(-) stem cell compartment. Survival of these cells after chemotherapy may lead to minimal residual disease (MRD) and subsequently to relapse. Therefore, the prognostic impact of stem cell frequency in CD34-positive AML was investigated.
  
  
  METHODS
  First, the leukemogenic potential of unpurified CD34(+)CD38(-) cells, present among other cells, was investigated in vivo using nonobese diabetic/severe combined immunodeficient mice transplantation experiments. Second, we analyzed whether the CD34(+)CD38(-) compartment at diagnosis correlates with MRD frequency after chemotherapy and clinical outcome in 92 AML patients.
  
  
  RESULTS
  In vivo data showed that engraftment of AML blasts in nonobese diabetic/severe combined immunodeficient mice directly correlated with stem cell frequency of the graft. In patients, a high percentage of CD34(+)CD38(-) stem cells at diagnosis significantly correlated with a high MRD frequency, especially after the third course of chemotherapy. Also, it directly correlated with poor survival. In contrast, total CD34(+) percentage showed no such correlations.
  
  
  CONCLUSIONS
  Both in vivo data, as well as the correlation studies, show that AML stem cell frequency at diagnosis offers a new prognostic factor. From our data, it is tempting to hypothesize that a large CD34(+)CD38(-) population at diagnosis reflects a higher percentage of chemotherapy-resistant cells that will lead to the outgrowth of MRD, thereby affecting clinical outcome. Ultimately, future therapies should be directed toward malignant stem cells.
authors.affiliation: Department of Hematology, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Anna
authors.initials: A
authors.lastname: van Rhenen
authors.forename: Nicole
authors.initials: N
authors.lastname: Feller
authors.forename: Angèle
authors.initials: A
authors.lastname: Kelder
authors.forename: August H
authors.initials: AH
authors.lastname: Westra
authors.forename: Elwin
authors.initials: E
authors.lastname: Rombouts
authors.forename: Sonja
authors.initials: S
authors.lastname: Zweegman
authors.forename: Marjolein A
authors.initials: MA
authors.lastname: van der Pol
authors.forename: Quinten
authors.initials: Q
authors.lastname: Waisfisz
authors.forename: Gert J
authors.initials: GJ
authors.lastname: Ossenkoppele
authors.forename: Gerrit Jan
authors.initials: GJ
authors.lastname: Schuurhuis
mesh_terms: D036541:ADP-ribosyl Cyclase / Q000032:analysis; D051997:ADP-ribosyl Cyclase 1; D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000032:analysis; D018952:Antigens, CD34 / Q000032:analysis; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007951:Leukemia, Myeloid / Q000145:classification / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008562:Membrane Glycoproteins; D008875:Middle Aged; D015999:Multivariate Analysis; D018365:Neoplasm, Residual / Q000378:metabolism / Q000473:pathology*; D014411:Neoplastic Stem Cells / Q000737:chemistry*; D011379:Prognosis; D016019:Survival Analysis
chemical_list: D015703:Antigens, CD; D018952:Antigens, CD34; D008562:Membrane Glycoproteins; D036541:ADP-ribosyl Cyclase; C498154:CD38 protein, human; D051997:ADP-ribosyl Cyclase 1