Cytogenetic subgroups in acute myeloid leukemia differ in proliferative activity and response to GM-CSF

The current study was undertaken to search for differences in the biology o f cytogenetic subgroups in patients with de novo acute myeloid leukemia (AM L), In addition, factors influencing the metabolism of cytosine arabinoside (araC) as the key agent of antileukemic activity were assessed. Bone marro w aspirates from 91 patients with newly diagnosed AML in whom karyotypes we re successfully obtained were analyzed: (1) for spontaneous proliferative a ctivity by H-3-thymidine (H-3-TdR) incorporation; (2) proliferative respons e to GM-CSF by in vitro incubation of blasts for 48 h with or without GM-CS F (100 U/ml) followed by an additional 4-h exposure to H-3-TdR (0.5 mu Ci/m l); and (3) parameters of araC metabolism comprising H-3-araC uptake in vit ro and the activities of polymerase alpha (poly a), deoxycytidine kinase (D CK) and deoxycytidine deaminase (DCD), According to the results of chromoso me analyses four cytogenetic subgroups were discriminated: (1) normal karyo types (n=38); (II) favorable karyotypes [t8;21), t(15;17), inv(18)](n=16); (III) unfavorable karyotypes [inv (3), -5, 5q-, t(6;9), +8, t (9;11), compl ex abnormalities] (n=20); (IV) karyotypes of unknown prognostic significanc e (n=17). Proliferative activity of leukemic blasts was significantly highe r in favorable karyotypes (group II) as compared to cases with unfavorable cytogenetics (group III) with median values and range for H-3-TdR uptake in group II of 2.48 pmol/10(5) cells (0.28-25.8) and in group III of 0.51 pmo l/10(5) cells (0.04-7.6) (P = 0.0096). The respective values in group I and group IV were 0.7 pmol/10(5) cells (0.0-6.7) and 0.98 pmol/10(5) cells (0. 0-4.0), respectively. Inversely, response to GM-CSF, as defined by an incre ase in H-3-TdR incorporation >1.5- fold over control values after 48 h of G M-CSF exposure, was significantly lower for patients with a favorable karyo type (group II) as compared to group I (P=0.04) and group III (P= 0.013). N o significant differences between karyotype groups I, 11, III and IV were f ound for H-3-araC incorporation, nor for the activities of poly a, DCK and DCD, These data demonstrate differences in the biology of cytogenetic subgr oups in AML which may partly explain the well established differences in cl inical outcome.