Abstract
Anthracyclines used in the treatment of acute myelogenous leukemia (AML) inhibit the activity of the mammalian topoisomerase II (topo II) isoforms, topo II α and topo IIβ. In 230 patients with non-M3 AML who received frontline ara-C/daunorubicin we determined expression of topo IIα and topo IIβ by RT-PCR and its relationship to immunophenotype (IP) and outcomes. Treatment outcomes were analyzed by logistic or Cox regression. In 211 patients, available for analysis, topo IIα expression was significantly lower than topo IIβ (P < 0.0001). In contrast to topo IIα, topo IIβ was significantly associated with blast percentage in marrow or blood (P = 0.0001), CD7 (P = 0.01), CD14 (P < 0.0001) and CD54 (P < 0.0001). Event free survival was worse for CD56-negative compared to CD56-high (HR = 1.9, 95% CI [1.0–3.5], p = 0.04), and overall survival was worse for CD-15 low as compared to CD15-high (HR = 2.2, 95% CI [1.1–4.2], p = 0.02). Ingenuity pathway analysis indicated topo IIβ and immunophenotype markers in a network associated with cell-to-cell signaling, hematological system development/function and inflammatory response. Topo IIβ expression reflects disease biology of highly proliferative disease and distinct IP but does not appear to be an independent variable influencing outcome in adult AML patients treated with anthracycline-based therapy.
Highlights
Standard induction therapy for acute myeloid leukemia (AML) consists of a combination of cytarabine and an anthracycline, such as daunorubicin or idarubicin[1,2]
We examined the expression of the topoisomerase II (topo II) isoforms and possible relationships of topo IIα and topo IIβ expression to immunophenotype (IP) and outcomes in de novo and secondary adult acute myelogenous leukemia (AML) blast samples from 230 patients enrolled in 4 SWOG studies who received ara-C/daunorubicin-based frontline chemotherapy
Additional regression analysis of IP with outcome measures revealed event free survival was worse for CD56-ve compared to CD56-high (HR = 1.9, 95% CI [1.0–3.5], p = 0.04), and overall survival was worse for CD15-low as compared to CD15-high (HR = 2.2, 95% CI [1.1–4.2], p = 0.02)
Summary
Standard induction therapy for acute myeloid leukemia (AML) consists of a combination of cytarabine (ara-C) and an anthracycline, such as daunorubicin or idarubicin[1,2]. While expression of topo IIα is cell cycle-dependent[7] topo IIβ levels remain unchanged during cell cycle progression[7,8,9] and are maximal in terminally differentiated tissues[8,10,11]. This difference in expression suggests that these two isoforms exert distinct functional roles in cellular processes that require topological changes in the DNA molecule. We examined the expression of the topo II isoforms and possible relationships of topo IIα and topo IIβ expression to immunophenotype (IP) and outcomes in de novo and secondary adult AML blast samples from 230 patients enrolled in 4 SWOG studies who received ara-C/daunorubicin-based frontline chemotherapy
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