Bcl-2 protein expression in normal human bone marrow precursors and in acute myelogenous leukemia
Porwit-MacDonald, A.; Ivory, K.; Wilkinson, S.; Wheatley, K.; Wong, L.; Janossy, G.
Leukemia 9(7): 1191-1198
1995
ISSN/ISBN: 0887-6924 PMID: 7543174 Document Number: 454728
The expression of bcl-2 protein that is involved in preventing apoptosis in hemopoietic and other cells was evaluated by quantitative flow cytometry in various subpopulations in the normal fetal bone marrow (FBM) and in different types of acute myelogenous leukemias (AML). In the FBM the highest bcl-2 levels (mean antibody binding capacity 51 times 10-3 molecules/cell) were found in CD34+ intermediate sized blasts and myeloblasts, while a CD34+ subset of CD10+ lymphoblasts had low bcl-2 content (8-10 times 10-3 molecules/cell) and the CD34-, CD10+ lymphoblasts were, as expected from previous studies, bcl-2- ( lt 5 times 10-3 molecules/cell). Variable levels of bcl-2 (5.1-222 times 10-3) were found in 43 tested cases of AML. The bcl-2 levels decrease with granulocytic and monocytic differentiation and, accordingly, cases of AML with M1 and M2 features showed significantly higher mean bcl-2 levels than the leukemias with promyelocytic (M3) or myelo-monocytic (M4/M5) features. Nevertheless, in seven cases of AML the bcl-2 levels were higher than seen in the normal FBM cells and none of these patients remain in remission after 2 years. Furthermore, in several AML cases intraclonal heterogeneity was observed. The undifferentiated smaller blasts with Class-II-dim display had higher bcl-2 content than the more differentiated larger blasts with more granular side scatter and Class-II-bright expression. In the same subsets of AML blasts the proliferative S-G-2-M fractions showed a reciprocal correlation to bcl-2 content. Thus the higher bcl-2 levels may give a survival advantage and confer some degree of drug resistance to the least differentiated blast populations. The multi-parameter analysis described in this paper, including a combined bcl-2 and cytokinetic analysis of phenotypically defined subgroups of AML blasts, may detect early population shifts during relapse and also guide combination drug therapy.