title: High proportion of leukemic stem cells at diagnosis is correlated with unfavorable prognosis in childhood acute myeloid leukemia.
abstract: In acute myeloid leukemia (AML), the leukemia-initiating cell is found within the CD34(+)/CD38(-) cell compartment. Over the last years evidence grew that AML is initiated and propagated by leukemic stem cells (LSCs). Conceivably, these most immature leukemia cells are more resistant to therapy and subsequently initiate relapse. The authors studied 17 patients with childhood AML treated according to the AML-BFM 98/04 protocol. At diagnosis, the authors determined the characteristic immunophenotype of the leukemic cells by flow cytometry and investigated the expression of CD34, CD38, and CD45 to define a population of immunophenotypically immature cells (CD34(+)/CD38(-)/CD45(-/low)) enriched for LSCs in many cases of AML. The authors compared the fraction of this population of all myeloid cells at diagnosis with event-free survival. Kaplan-Meier analysis revealed significant higher event free survival of patients with low CD34(+)/CD38(-)/CD45(-/low) cell proportion (<0.68%) compared to patients with high burden of this population (>0.83%; log-rank P < .04). This correlation was not found for the total number of CD34(+) cells. This is the first study to show that a higher proportion of immature CD34(+)/CD38(-)/CD45(-/low) blasts at diagnosis correlates with unfavorable prognosis in childhood AML. The results suggest that a large CD34(+)/CD38(-)/CD45(-/low) population reflects a higher fraction of LSCs, leading to increased chemotherapy resistance and elevated relapse rate. Thus the initial frequency of CD34(+)/CD38(-)/CD45(-/low) cells may serve as a prognostic marker in pediatric AML. Future treatment in childhood AML should specifically target this immature population as well as the mature blast population.
authors.affiliation: Department of Hematology/Oncology, University Children's Hospital, Tübingen, Germany.
authors.forename: Kai-Erik
authors.initials: KE
authors.lastname: Witte
authors.forename: Jörg
authors.initials: J
authors.lastname: Ahlers
authors.forename: Iris
authors.initials: I
authors.lastname: Schäfer
authors.forename: Maya
authors.initials: M
authors.lastname: André
authors.forename: Gunter
authors.initials: G
authors.lastname: Kerst
authors.forename: Hans-Gerhard
authors.initials: HG
authors.lastname: Scheel-Walter
authors.forename: Carl Philipp
authors.initials: CP
authors.lastname: Schwarze
authors.forename: Matthias
authors.initials: M
authors.lastname: Pfeiffer
authors.forename: Peter
authors.initials: P
authors.lastname: Lang
authors.forename: Rupert
authors.initials: R
authors.lastname: Handgretinger
authors.forename: Martin
authors.initials: M
authors.lastname: Ebinger
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000378:metabolism; D000293:Adolescent; D018952:Antigens, CD34 / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002648:Child; D002675:Child, Preschool; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D016130:Immunophenotyping; D007223:Infant; D015470:Leukemia, Myeloid, Acute / Q000145:classification / Q000175:diagnosis* / Q000188:drug therapy / Q000378:metabolism; D017493:Leukocyte Common Antigens / Q000378:metabolism; D008297:Male; D018365:Neoplasm, Residual / Q000175:diagnosis*; D014411:Neoplastic Stem Cells / Q000473:pathology*; D011379:Prognosis; D015996:Survival Rate
chemical_list: D018952:Antigens, CD34; D014408:Biomarkers, Tumor; D017493:Leukocyte Common Antigens; D051997:ADP-ribosyl Cyclase 1