Proliferation patterns in acute myeloid leukemia: leukemic clonogenic growth and in vivo cell cycle kinetics

Abstract

In a prospective study of 33 newly diagnosed patients with acute myeloid leukemia (AML), we analyzed the relationship of proliferation parameters with clinical parameters, response to induction therapy, and survival. The median follow-up was 26 months. The proliferative capacity of the leukemic progenitor cells was studied using colony-forming assays (number of colony-forming units, growth pattern, and spontaneous clonogenic growth capacity). The cell kinetic parameters of the bone marrow blasts were determined by in vivo labeling with iododeoxyuridine and subsequent flow cytometry: labeling index (LI), DNA synthesis time (Ts), potential doubling time. No or only weak relationships were observed between the experimental and clinical parameters such as age, sex, % blasts, white blood cell count, FAB subtype, cytogenetics, and % CD 34+ cells. This suggests that clonogenic growth and cell cycle kinetics of bone marrow blasts are independent cell biologic properties of AML. No association between the proliferation parameters and induction response rate was noticed. Analysis of the overall survival and event-free survival revealed trends to longer survival rates in patients with a below-median LI (< or = 7.6%) and below-median Ts value (< or = 14.3 h). These trends were more pronounced in the group of de novo AML (n = 23), where the prolonged event-free survival in patients with below-median Ts reached statistical significance (p = 0.02). None of the other parameters appeared significantly correlated with survival, although there was a trend to longer survival rates in patients who had no spontaneous clonogenic growth capacity (p = 0.13). In conclusion, proliferation parameters in leukemic cells provide additional information on the cell biologic characteristics of AML, and these parameters may have prognostic value for response and duration of survival in AML.

In vitro growth in acute myeloblastic leukaemia: relationship with other clinico‐biological characteristics of the disease

“…The present study shows that clonogenic growth is highly variable in AML, confirming previous results from both ourselves and other groups ( del Cañizo et al , 1994 ; Almeida et al , 1995 ; Brons et al , 1993 ). When the PE was analysed we did not observe any significant difference between the secondary and de novo AML cases.…”

“…However, when CD34 expression was analysed we observed that the PE was similar in positive and negative cases. In accordance with our results, Brons et al (1993 ) did not find any correlation between the proliferative capacity of blast cells and CD34 expression. In a previous paper ( del Cañizo et al , 1997 ) we showed that CD34 expression did not have the same significance in AML as in normal haemopoiesis, perhaps because blast cells in AML frequently display phenotypic aberrancies and thus the antigen expression may stray from the normal differentiation pathway.…”

Impaired DNA damage response — An Achilles' heel sensitizing cancer to chemotherapy and radiotherapy

“…In fact, antitumor strategies were designed to schedule chemotherapy based on the cell cycle kinetics of tumors (Braunschweiger and Schiffer, 1980; Braunschweiger et al, 1979; Hill, 1975; Karp and Burke, 1976). Cytokinetic paramaters were considered as predictive markers of tumor sensitivity to treatment (Amadori et al, 2004; Brons et al, 1993). Attempts at cell synchronization in treatment protocols aimed to effectively target cancer cells, however, did not yield the expected results (Kremer et al, 1976).…”

ID1 and ID2 are retinoic acid responsive genes and induce a G0/G1 accumulation in acute promyelocytic leukemia cells

“…Bivariate staining for BrdUrd incorporation and DNA content and calculation of the cell cycle time was performed as described previously. 24 Flow cytometric analysis of the results was performed on a Coulter Epics Elite flowcytometer (Beckman Coulter, Miami, FL, USA).…”