title: Evidence for malignant transformation in acute myeloid leukemia at the level of early hematopoietic stem cells by cytogenetic analysis of CD34+ subpopulations.
abstract: Acute myeloid leukemia (AML) is a heterogenous disease according to morphology, immunophenotype, and genetics. The retained capacity of differentiation is the basis for the phenotypic classification of the bulk population of leukemic blasts and the identification of distinct subpopulations. Within the hierarchy of hematopoietic development and differentiation it is still unknown at which stage the malignant transformation occurs. It was our aim to analyze the potential involvement of cells with the immunophenotype of pluripotent stem cells in the leukemic process by the use of cytogenetic and cell sorting techniques. Cytogenetic analyses of bone marrow aspirates were performed in 13 patients with AML (11 de novo and 2 secondary) and showed karyotype abnormalities in 10 cases [2q+, +4, 6p, t(6:9), 7, +8 in 1 patient each and inv(16) in 4 patients each]. Aliquots of the samples were fractionated by fluorescence-activated cell sorting of CD34+ cells. Two subpopulations, CD34+/CD38- (early hematopoietic stem cells) and CD34+/CD38+ (more mature progenitor cells), were screened for karyotype aberations as a marker for leukemic cells. Clonal abnormalities and evaluable metaphases were found in 8 highly purified CD34+/CD38- populations and in 9 of the CD34+/CD38- specimens, respectively. In the majority of cases (CD34+/CD38-, 6 of 8 informative samples; CD34+/CD38+, 5 of 9 informative samples), the highly purified CD34+ specimens also contained cytogenetically normal cells. Secondary, progression-associated chromosomal changes (+8, 12) were identified in the CD34+/CD38- cells of 2 patients. We conclude that clonal karyotypic abnormalities are frequently found in the stem cell-like (CD34+/CD38-) and more mature (CD34+/CD38+) populations of patients with AML, irrespective of the phenotype of the bulk population of leukemic blasts and of the primary or secondary character of the leukemia. Our data suggest that, in AML, malignant transformation as well as disease progression may occur at the level of CD34+/CD38- cells with multilineage potential.
authors.affiliation: Department of Hematology and Oncology, University of Göttingen, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Haase
authors.forename: M
authors.initials: M
authors.lastname: Feuring-Buske
authors.forename: S
authors.initials: S
authors.lastname: Könemann
authors.forename: C
authors.initials: C
authors.lastname: Fonatsch
authors.forename: C
authors.initials: C
authors.lastname: Troff
authors.forename: W
authors.initials: W
authors.lastname: Verbeek
authors.forename: A
authors.initials: A
authors.lastname: Pekrun
authors.forename: W
authors.initials: W
authors.lastname: Hiddemann
authors.forename: B
authors.initials: B
authors.lastname: Wörmann
mesh_terms: D000208:Acute Disease; D000328:Adult; D000368:Aged; D000782:Aneuploidy; D018952:Antigens, CD34; D015415:Biomarkers; D002454:Cell Differentiation; D019070:Cell Lineage; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002869:Chromosome Aberrations; D002999:Clone Cells / Q000473:pathology; D005260:Female; D006412:Hematopoietic Stem Cells / Q000473:pathology*; D006801:Humans; D016130:Immunophenotyping; D007951:Leukemia, Myeloid / Q000145:classification / Q000235:genetics / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000473:pathology*
chemical_list: D018952:Antigens, CD34; D015415:Biomarkers