BAALC and ERG expression levels are associated with outcome and distinct gene and microRNA expression profiles in older patients with de novo cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B study

Abstract

BAALC and ERG expression levels are prognostic markers in younger (< 60 years) cytogenetically normal acute myeloid leukemia (CN-AML) adults; their prognostic impact in older (≥ 60 years) patients requires further investigation. We evaluated pretreatment expression of BAALC and ERG in 158 de novo patients treated on cytarabine/daunorubicin-based protocols. The patients were also characterized for other established molecular prognosticators. Low BAALC and ERG expression levels were associated with better outcome in univariable and multivariable analyses. Expression levels of both BAALC and ERG were the only factors significantly associated with overall survival upon multivariable analysis. To gain biological insights, we derived gene expression signatures associated with BAALC and ERG expression in older CN-AML patients. Furthermore, we derived the first microRNA expression signatures associated with the expression of these 2 genes. In low BAALC expressers, genes associated with undifferentiated hematopoietic precursors and unfavorable outcome predictors were down-regulated, whereas HOX genes and HOX-gene-embedded microRNAs were up-regulated. Low ERG expressers presented with down-regulation of genes involved in the DNA-methylation machinery, and up-regulation of miR-148a, which targets DNMT3B. We conclude that in older CN-AML patients, low BAALC and ERG expression associates with better outcome and distinct gene and microRNA expression signatures that could aid in identifying new targets and novel therapeutic strategies for older patients.

Figure 1

Outcome of cytogenetically normal older AML patients according to BAALC expression levels. (A) DFS. (B) OS.

Figure 2

Outcome of cytogenetically normal older AML patients according to ERG expression levels. (A) DFS. (B) OS.

Figure 3

Outcome of cytogenetically normal older AML patients according to a combination of BAALC and ERG expression levels. Patients with low expression of BAALC or ERG, or both, were compared with those having high expression of both BAALC and ERG. (A) DFS. (B) OS.

Figure 4

Heat maps of the BAALC signatures. Derived gene expression (A) and microRNA expression signatures (B) associated with BAALC expression in the group of CN-AML patients ≥ 60 years. Patients are ordered from left to right by increasing BAALC expression. Expression values of the gene probe sets (microRNA probes) are represented by color, with blue indicating expression less than and red indicating expression greater than the median value for the given gene probe set (microRNA probe). For the gene expression heat map, up- and down-regulated genes mentioned in the text are indicated.

Figure 5

Heat maps of the ERG signatures. Derived gene expression (A) and microRNA expression signatures (B) associated with ERG expression in the group of CN-AML patients ≥ 60 years. Patients are ordered from left to right by increasing ERG expression. Expression values of the gene probe sets (microRNA probes) are represented by color, with blue indicating expression less than and red indicating expression greater than the median value for the given gene probe set (microRNA probe). For the gene expression heat map, up- and down-regulated genes mentioned in the text are indicated.