KRAS overexpression independent of RAS mutations confers an adverse prognosis in cytogenetically normal acute myeloid leukemia.

Jing-Dong Zhou,Xi-Xi Li,Wei Zhang,Dong-Ming Yao,Zhao-Qun Deng,Ji-Chun Ma,Hong Guo,Ting-Juan Zhang,Jun Qian,Jiang Lin

doi:10.18632/oncotarget.19798

Abstract

The prognostic value of RAS mutations has been systematically investigated in acute myeloid leukemia (AML). However, clinical significance of RAS expressions in AML remains poorly determined. To explore the clinical significance, we analyzed KRAS and NRAS expressions in 143 de novo AML patients by real-time quantitative PCR. KRAS and NRAS expressions were significantly up-regulated in AML patients. KRAS and NRAS mutations were identified in 4% (6/143) and 8% (12/143) of these patients, respectively. However, no significant association was observed between RAS mutations and expressions. High KRAS expression was associated with older age, higher white blood cells, and a tendency of higher platelets, whereas high NRAS expression was only correlated with older age. Complete remission (CR) rate and overall survival of AML patients were adversely affected by KRAS overexpression, but not NRAS overexpression. Multivariate analysis revealed that KRAS acted as an independent prognostic predictor in cytogenetically normal AML (CN-AML). Moreover, the prognostic value of KRAS expression was validated using the published data from Gene Expression Omnibus datasets. In the follow-up patients, KRAS expression rather than NRAS expression in CR time tended to decrease compared to newly diagnosis time, and both KRAS and NRAS expressions were significantly increased when in relapse time. Our findings revealed that RAS overexpression and mutations were common events in AML with potential therapeutic target value. KRAS overexpression independent of RAS mutations conferred an adverse prognosis in CN-AML.

Highlights

Acute myeloid leukemia (AML) is an aggressive hematopoietic malignancy associated with severe morbidity and poor clinical outcome [1, 2]
Increased NRAS expression was found in acute myeloid leukemia (AML) patients compared with controls (P=0.044, Figure 1B), and identified in 37/143 (26%) of AML patients based on the cut-off value
Patients with and without NRAS mutation showed similar level of KRAS and NRAS expression. All these results suggested that RAS expressions were not correlated with RAS mutations in AML

Summary

Introduction

Acute myeloid leukemia (AML) is an aggressive hematopoietic malignancy associated with severe morbidity and poor clinical outcome [1, 2]. In approximately 50% of AML patients, no cytogenetic abnormality is detectable at the diagnosis time, often called as cytogenetically normal AML (CN-AML) [1, 2]. Such patients are in an intermediate-risk prognostic category, but among them are subgroups of patients who www.impactjournals.com/oncotarget have molecular markers associated with either a favorable prognosis or an unfavorable prognosis [2,3,4]. Further refinement of relevant molecular alterations in different AML subgroups might eventually result in more individual treatment approaches and potentially improve outcome

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Conclusion