title: Effect of chemotherapy for acute myelogenous leukemia on hematopoietic and fibroblast marrow progenitors.
abstract: Since reduced marrow cellularity and prolonged pancytopenia following autologous bone marrow transplantation (ABMT) have been frequently observed in patients with acute myelogenous leukemia (AML) included in the AML10 GIMEMA/EORTC trial, the question was raised to what extent hematopoietic and microenvironmental progenitor cells were involved in these patients. Marrow hematopoietic progenitors were investigated by a short-term methylcellulose assay quantitating multipotent CFU-Mix, erythroid BFU-E and granulocyte-macrophage CFU-GM, as well as a long-term assay quantitating long-term culture-initiating cells (LTC-IC). The marrow microenvironment was studied by evaluating the incidence of fibroblastoid progenitors (CFU-F) and the capacity of stromal layers to support allogeneic hematopoietic progenitors. As compared to normal controls (n = 57), AML patients (n = 26) showed a statistically significant reduction of the mean (+/-s.e.m.) number of CFU-Mix (5.3 +/- 0.6 vs 0.8 +/- 0.2, P < or = 0.0001), BFU-E (68 +/- 5 vs 20 +/- 4, P < or = 0.0001), CFU-GM (198 +/- 11 vs 144 +/- 15, P < or = 0.008), and LTC-IC (302 +/- 46 vs 50 +/- 8, P < or = 0.001). The mean (+/-s.e.m.) incidence of marrow CFU-F was not significantly reduced as compared to normal controls (48 +/- 6 vs 52 +/- 7, P < or = 0.73). Seventeen AML stromal layers were tested for their capacity to support the growth of allogeneic hematopoietic progenitors. Seven samples failed to support any progenitor cell growth, seven had a significantly lower supportive activity as compared to normal stromal layers (13 +/- 5 vs 249 +/- 56, P < or = 0.002), whereas three cultures could not be analyzed due to contamination. In conclusion, induction and consolidation regimens used in AML patients of the AML10 protocol induce a markedly defective in vitro growth of primitive hematopoietic progenitors and a severe functional defect of marrow stroma. The association of hematopoietic with microenvironmental damage might play a key role in the delayed hematopoietic regeneration observed following ABMT in patients of the AML10 trial.
authors.affiliation: Department of Hematology, University of Parma, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Carlo-Stella
authors.forename: A
authors.initials: A
authors.lastname: Tabilio
authors.forename: E
authors.initials: E
authors.lastname: Regazzi
authors.forename: D
authors.initials: D
authors.lastname: Garau
authors.forename: R
authors.initials: R
authors.lastname: La Tagliata
authors.forename: S
authors.initials: S
authors.lastname: Trasarti
authors.forename: C
authors.initials: C
authors.lastname: Andrizzi
authors.forename: M
authors.initials: M
authors.lastname: Vignetti
authors.forename: G
authors.initials: G
authors.lastname: Meloni
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001853:Bone Marrow / Q000187:drug effects* / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D003114:Colony-Forming Units Assay; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000473:pathology; D006412:Hematopoietic Stem Cells / Q000187:drug effects* / Q000473:pathology; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000097:blood / Q000188:drug therapy* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D017154:Stromal Cells / Q000187:drug effects / Q000473:pathology