Increased anti-apoptotic (Bcl-2+) and decreased proliferative (Ki-67+) cell fractions during the different maturation stages of bone marrow cell populations in MDS and AML: The potential diagnostic impact of the Bcl-2:Ki-67 ratio.

Abstract

The relationship between apoptosis inhibition and cell proliferation was studied during the maturation stages of erythropoiesis, granulopoiesis, and monopoiesis in patients with myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). The anti-apoptotic and proliferative cell fractions were determined in bone marrow aspirates derived from 25 MDS patients and 25 AML patients and compared to 50 nonmalignant cases, using antibodies to Bcl-2 and Ki-67, respectively. These were applied along with ten-color flow cytometry of maturation markers for the three hematopoietic cell lineages. Next, the Bcl-2:Ki-67 ratio was determined as the ratio between the Bcl-2+ and Ki-67+ cell fractions of the specific hematopoietic cell lineages, both in total and during the different stages of maturation. Bone marrow samples from MDS and AML patients showed a significant increase in the anti-apoptotic cell fraction and a reduced proliferative cell compartment compared to non-malignant cases. Overall, the anti-apoptotic cell fraction was particularly increased in the more mature stages, while the proliferative cell fractions were decreased more frequently in the immature stages. These changes varied among different hematopoietic cell lineages. The erythropoietic maturation process showed the most significant differences in both Ki-67+ and Bcl-2+ cell fractions when comparing MDS and AML to non-malignant cases. This difference was restricted to that of the Bcl-2+ cell fractions in the granulopoiesis and that of the Ki-67+ cell fraction of the monopoiesis. All three hematopoietic cell lineages encompass a small fraction of cells (up to 10%) that concurrently exhibit anti-apoptotic and proliferative marker expression. Although MDS and AML patients displayed considerable variability in their anti-apoptotic and proliferation index, the Bcl-2:Ki-67 ratio resulted in a clear separation between the malignant and non-malignant cases. Incorporating this combination of the Bcl-2 and Ki-67 markers into the study of MDS and AML and in future diagnostic workups may provide important insights into the biological behavior of these blood-borne neoplasms and facilitate personalized therapy decisions for patients.