BAALC expression: a suitable marker for prognostic risk stratification and detection of residual disease in cytogenetically normal acute myeloid leukemia

S Weber,N Nadarajah,M Meggendorfer,S Jeromin,T Alpermann,A Fasan,T Haferlach,W Kern,A Kohlmann,C Eder,F Dicker,C Haferlach,S Schnittger

doi:10.1038/bcj.2013.71

Abstract

High brain and acute leukemia, cytoplasmic (BAALC) expression defines an important risk factor in cytogenetically normal acute myeloid leukemia (CN-AML). The prognostic value of BAALC expression in relation to other molecular prognosticators was analyzed in 326 CN-AML patients (<65 years). At diagnosis, high BAALC expression was associated with prognostically adverse mutations: FLT3 internal tandem duplication (FLT3-ITD) with an FLT3-ITD/FLT3 wild-type (wt) ratio of ⩾0.5 (P=0.001), partial tandem duplications within the MLL gene (MLL-PTD) (P=0.002), RUNX1 mutations (mut) (P<0.001) and WT1mut (P=0.001), while it was negatively associated with NPM1mut (P<0.001). However, high BAALC expression was also associated with prognostically favorable biallelic CEBPA (P=0.001). Survival analysis revealed an independent adverse prognostic impact of high BAALC expression on overall survival (OS) and event-free survival (EFS), and also on OS when eliminating the effect of allogeneic stem cell transplantation (SCT) (OSTXcens). Furthermore, we analyzed BAALC expression in 416 diagnostic and follow-up samples of 66 patients. During follow-up, BAALC expression correlated with mutational load or expression levels, respectively, of other minimal residual disease markers: FLT3-ITD (r=0.650, P<0.001), MLL-PTD (r=0.728, P<0.001), NPM1mut (r=0.599, P<0.001) and RUNX1mut (r=0.889, P<0.001). Moreover, a reduction in BAALC expression after the second cycle of induction chemotherapy was associated with improved EFS. Thus, our data underline the utility of BAALC expression as a marker for prognostic risk stratification and detection of residual disease in CN-AML.

Highlights

Acute myeloid leukemia (AML) is a heterogeneous disease with respect to clinical picture and therapeutic outcome, partly reflected by differences in cytogenetics and molecular genetics.In approximately 55% of patients with AML, cytogenetic aberrations can be used for risk stratification, but there is still a large subgroup of patients who lack informative chromosome markers.[1]
The most useful markers implicated in prognostication are NPM1 mutations, FLT3 internal tandem duplication (FLT3-ITD),[3,4,5,6,7] biallelic CEBPA mutations,[8] partial tandem duplications within the MLL gene (MLL-PTD), RUNX1mut and ASXL1mut.[9,10,11,12]
Examination time points BAALC mRNA expression was analyzed in 326 de novo AML patients (o65 years) with cytogenetically normal acute myeloid leukemia (CN-AML) by the use of quantitative real-time PCR

Summary

Introduction

Acute myeloid leukemia (AML) is a heterogeneous disease with respect to clinical picture and therapeutic outcome, partly reflected by differences in cytogenetics and molecular genetics.In approximately 55% of patients with AML, cytogenetic aberrations can be used for risk stratification, but there is still a large subgroup of patients who lack informative chromosome markers.[1]. In terms of molecular characteristics, patients with high BAALC expression were more likely to harbor FLT3-ITD (71/163, 43.6% vs 53/163, 32.5%, P 1⁄4 0.052), MLL-PTD (21/163, 12.9% vs 5/163, 3.1%, P 1⁄4 0.002) and to carry mutations in RUNX1 (31/163, 19.0% vs 2/162, 1.2%, Po0.001), CEBPA (23/163, 14.1% vs 7/163, 4.3%, P 1⁄4 0.003) or WT1 (22/163, 13.5% vs 5/162, 3.1%, P 1⁄4 0.001), whereas NPM1mut was negatively correlated (71/163, 43.6% vs 138/163, 84.7%, Po0.001).

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Conclusion