Relative receptor tyrosine kinases and anti-apoptotic transcripts hold potential for predicting inferior outcome in adult acute myeloid leukemia: a prospective pilot study

Abstract

Introduction: Acute myeloid leukemia is characterized by accumulation of immature cells because of imbalance between proliferation and apoptosis. In AML, simultaneous expression of proliferative (FLT-3, c-KIT) and antiapoptotic genes (BCL-2), are unknown. Patients and Methods: We prospectively assessed proliferative and antiapoptotic gene transcripts using Taqman probe chemistry in 48 adult AML patients. A stepwise Cox regression model was applied for independent prognostic factors. Results: Thirty-two of 48 (75%) patients achieved complete remission. At follow-up ranging from 0.5 to 57.3 months, event-free survival (EFS) was 26.9 ± 6.3% (range, 15.5%-39.6%) and OS 34.5 ± 7.46% (range, 20.5%-48.9%). High white blood cell count correlated with an inferior complete remission rate (P = .021). Cytogenetics and FLT-3 internal tandem duplication did not predict EFS or OS. The transcripts of FLT-3, c-KIT, and BCL-2 showed a significant linear association with each other in Pearson correlation (FLT-3 vs. c-KIT: R = 0.8234; P < .001; c-KIT vs. BCL-2: R = 0.3377; P = .01; FLT-3 vs. BCL-2: R = 0.3815; P = .007). In a validation cohort (Microarray Data Set GSE1159) of adult AML patients, the global gene expression profile depicted a similar interrelationship. Patients with a greater platelet count were associated with increased transcript levels of BCL-2 (P = .034). In univariate analysis, a high transcript level of FLT-3 and high transcript ratio of FLT-3/BCL-2 and FLT-3 and c-KIT/BCL-2 significantly predicted OS (P = .043, .028, and .028, respectively). In a stepwise Cox regression model, high FLT-3 and c-KIT/BCL-2 ratio predicted OS (HR, 2.29). Conclusion: To our knowledge, this is the first study that evaluated proliferative and antiapoptotic transcripts simultaneously, and results have shown that it is the relative levels of these transcripts that determine outcome in AML patients rather than their expression in isolation.