High BAALC Research Articles

High BAALC expression associates with other molecular prognostic markers, poor outcome, and a distinct gene-expression signature in cytogenetically normal patients younger than 60 years with acute myeloid leukemia: a Cancer and Leukemia Group B (CALGB) study

AbstractBAALC expression is considered an independent prognostic factor in cytogenetically normal acute myeloid leukemia (CN-AML), but has yet to be investigated together with multiple other established prognostic molecular markers in CN-AML. We analyzed BAALC expression in 172 primary CN-AML patients younger than 60 years of age, treated similarly on CALGB protocols. High BAALC expression was associated with FLT3-ITD (P = .04), wild-type NPM1 (P < .001), mutated CEBPA (P = .003), MLL-PTD (P = .009), absent FLT3-TKD (P = .005), and high ERG expression (P = .05). In multivariable analysis, high BAALC expression independently predicted lower complete remission rates (P = .04) when adjusting for ERG expression and age, and shorter survival (P = .04) when adjusting for FLT3-ITD, NPM1, CEBPA, and white blood cell count. A gene-expression signature of 312 probe sets differentiating high from low BAALC expressers was identified. High BAALC expression was associated with overexpression of genes involved in drug resistance (MDR1) and stem cell markers (CD133, CD34, KIT). Global microRNA-expression analysis did not reveal significant differences between BAALC expression groups. However, an analysis of microRNAs that putatively target BAALC revealed a potentially interesting inverse association between expression of miR-148a and BAALC. We conclude that high BAALC expression is an independent adverse prognostic factor and is associated with a specific gene-expression profile.

Wilms Tumor 1 (WT1) Gene Mutations Predict Poor Outcome in Adults with Cytogenetically Normal (CN) Acute Myeloid Leukemia (AML): A Cancer and Leukemia Group B (CALGB) Study.

The WT1 gene on chromosome 11p13 encodes a zinc-finger protein regulating gene transcription. A recent study conducted on 70 CN-AML patients (pts) found that 7 (10%) harbored WT1 mutations (WT1mut) and suggested that WT1mut are associated with failure to achieve complete remission (CR) (Summers et al., Leukemia 2007; 21:550). However, the prognostic impact of WT1mut remains to be elucidated in a larger set of homogeneously treated adults with de novo CN-AML and in the context of established prognostic molecular markers. We studied the prevalence and prognostic impact of WT1mut in 196 younger [<60 years (yrs)] adults with de novo CN-AML who were intensively treated on frontline CALGB protocols incorporating autologous stem cell transplantation for consolidation, i.e. 9621 or 19808. The median follow-up for pts alive was 4.2 yrs (range, 1.2–8.9 yrs). Diagnostic bone marrow and/or blood specimens were studied for WT1mut by denaturing high-performance liquid chromatography and DNA direct sequencing. The samples were also analyzed for FLT3-ITD, FLT3-TKD, MLL-PTD, NPM1 and CEBPA mutations, and ERG and BAALC expression levels. Twenty-one (11%) of the 196 pts had WT1mut [15 had WT1mut in exon 7 (WT1mut7), 5 WT1mut in exon 9 (WT1mut9) and 1 WT1mut in both exons]. WT1mut7 were frameshift or nonsense mutations predicted to result in a truncated WT1 protein; WT1mut9 were missense mutations leading to single amino-acid substitutions. At diagnosis, WT1mut pts had higher white blood cell counts (WBC; P=0.01), more frequently harbored FLT3-ITD (P=0.06) and were more often high ERG (P=0.01) and high BAALC (P=0.006) expressers than unmutated WT1 (WT1wt) pts. While CR rates were not significantly different between WT1mut and WT1wt pts (76% vs 84%, P=0.36), WT1mut pts had worse disease-free survival [(DFS); P<0.001; 3-yr DFS rates, 13% vs 50%; Figure A] and worse overall survival [(OS); P<0.001; 3-yr OS rates, 10% vs 56%; Figure B] than WT1wt pts. In a multivariable analysis, WT1mut independently predicted worse DFS (P=0.009) when controlling for CEBPA (CEBPAmut vs CEBPAwt, P=0.005) and FLT3-ITD/NPM1 risk status (FLT3-ITD-negative and NPM1mut vs all other combinations of FLT3-ITD and NPM1 mutation status, P<0.001). The risk of relapse was 2.9 times higher for WT1mut pts than for WT1wt pts (95% CI: 1.3–6.3). WT1mut also independently predicted worse OS (P<0.001), and conferred a 3.6 times higher risk of death compared with WT1wt pts (95% CI: 1.8–7.2), when controlling for CEBPA (P=0.02), FLT3-ITD/NPM1 risk status (P<0.001), and WBC (P=0.01). In conclusion, we show here for the first time, in a relatively large set of intensively treated younger CN-AML pts, that WT1mut independently predicts very poor outcome. We propose that in future trials, WT1mut analysis should be considered for molecularly-based risk assessment and risk-adapted treatment stratification of CN-AML pts. [Display omitted]

High BAALC expression associates with other molecular prognostic markers, poor outcome and a distinct gene expression signature in cytogenetically normal acute myeloid leukemia (CN AML): A Cancer and Leukemia Group B (CALGB) study

7013 Background: High BAALC expression predicts poor outcome in CN AML patients (pts). Yet, little is known about BAALC's function or its relation to other prognostic markers. We evaluated BAALC expression in the context of molecular markers and clinical outcome in 172 de novo CN AML adults, aged &lt;60 years (y) treated on similar CALGB protocols (9621 and 19808). Methods: BAALC expression was measured by quantitative real-time RT-PCR in pretreatment blood samples. Pts were grouped as high (n=86) or low BAALC (n=86) expressers using the median expression value, by protocol, as a cutoff. Gene expression profiling (Affymetrix U133 plus 2.0 GeneChip) was performed on high (n=26) and low (n=24) pts. Results: BAALC expression was associated with several molecular markers ( Table ). Complete remission (CR) rate was lower in high BAALC pts (79% v 90%), for whom achieving CR was almost 4 times less likely than for low BAALC pts (P=.02; odds ratio=0.27), after adjusting for age (P=.004), ERG expression (P=.05) and white blood cell count (WBC; P=.04). With a median follow-up of 4.3 y, high BAALC pts had shorter overall survival (OS) (P=.002; 3-y OS: 42% v 59%). In a multivariable model, high BAALC provided further adverse prognostic information (P=.06; hazard ratio=1.66) independent of FLT3 ITD (P&lt;.001), WBC (P=.007) and NPM1 (P=.02). A gene expression signature was identified consisting of 312 probe sets differentially expressed (P&lt;.001) between BAALC groups. High BAALC was associated with overexpression of, among other genes, PROM1, CD34 and KIT indicating a less differentiated phenotype in these pts. Conclusions: Although associated with other prognostic markers, high BAALC expression independently predicts outcome and is associated with a distinct gene expression profile, potentially identifying new therapeutic targets in this pt subset. No significant financial relationships to disclose. [Table: see text]

Identification of a new subgroup of adult acute T-lymphoblastic leukemia (T-ALL) with a very favorable outcome using low ERG and BAALC expression

7014 Background: High expression of the oncogenic ETS transcription factor ERG is an independent adverse prognostic factor in T-ALL and acute myeloid leukemia (AML). The gene BAALC similarly shows high expression in hematopoietic progenitors, downregulation with onset of differentiation, and prognostic significance in AML. Therefore, we assessed whether combined expression of ERG and BAALC would better predict outcome in T-ALL. Methods: ERG and BAALC mRNA expression was determined by realtime RT-PCR in pretherapy bone marrow of 152 adults with newly diagnosed T-ALL treated on German ALL protocols (05/93, 06/99). Patients (pts) were designated low (n=76) or high (n=76) ERG expressers based on median ERG expression and as low (n=111) or high (n=37) BAALC grouping the lower quartiles 1–3 vs. quartile 4. HOX11 and HOX11L2 expression was determined and immunophenotyping differentiated 3 T-ALL groups (early, thymic, mature). Results: High BAALC expression correlated with immature T-ALL with a higher frequency of early T-ALL (P&lt;0.0001), CD34 positivity (P&lt;0.0001), co-expression of myeloid markers (CD13 and/or CD33; P=0.03), and high ERG expression (P=0.02). Pts with high BAALC had fewer complete remissions (73% vs. 89%, P=0.03) and a higher relapse rate (67% vs. 32%, P=0.01) than low BAALC pts. Excluding 33 pts that had received stem cell transplantation (SCT), high expression of ERG (P=0.002) and of BAALC (P=0.0004) was associated with inferior relapse-free survival (RFS) and overall survival (OS, ERG: P=0.004; BAALC: P=0.0001) compared to low expression of ERG and BAALC, respectively. In contrast, pts with low expression of both ERG and BAALC had the most favorable outcome (5y-RFS: low ERG/low BAALC 81% vs. high ERG and/or high BAALC 33%, P&lt;0.0001; 5y-OS: low ERG/low BAALC 69% vs. high ERG and/or high BAALC 26%, P=0.0001). On multivariable analysis low ERG/low BAALC expression was of independent favorable prognostic significance (RFS, HR: 0.18, P=0.0003; OS, HR: 0.3, P=0.001); the only other prognostic factor was the immunophenotype. Conclusions: Low expression of both ERG and BAALC identifies T-ALL pts with a distinctly favorable long term outcome, thus detecting pts that may not benefit from further treatment intensification including SCT. No significant financial relationships to disclose.

Risk Assessment in Patients with Acute Myeloid Leukemia and a Normal Karyotype

The recognition of a number of leukemia-specific cytogenetic abnormalities and their role as independent prognostic factors have provided considerable insights into leukemia pathogenesis and have paved the way to adopt risk-adapted treatment. However, approximately 50% of newly diagnosed acute myeloid leukemia (AML) have a normal karyotype. There has therefore been much interest in identifying molecular markers that could help to improve the prognostic stratification of patients with normal-karyotype AML. Consecutive untreated AML patients (n = 67) from a single institution all with normal karyotype were analyzed for the presence of mutations in the myeloid transcription factor gene CEBPA (for CCAAT/enhancer binding protein-alpha), for internal tandem duplications (ITD) of the tyrosine kinase receptor gene FLT3 (for fms-like tyrosine kinase 3), and for expression of the BAALC gene (for brain and acute leukemia, cytoplasmic). 17.9% of normal-karyotype AML had mutations in the CEBPA gene, and 28.4% had FLT3-ITD; 65.7% (44 of 67) had high BAALC expression and 34.3% (23 of 67) had low BAALC expression. Patients with CEBPA mutations had a very favorable course of their disease. Median disease-free survival (DFS) and overall survival (OS) were 33.5 and 45.5 months, respectively, compared with 10 (e.g., 12 months in patients without CEBPA mutations; P = 0.0017; P = 0.0007). AML patients with FLT3-ITD had significantly shorter median DFS (P = 0.0328) and OS (P = 0.0148) than patients without FLT3-ITD. High BAALC expression predicted for a shorter DFS (P = 0.0152) and OS (P = 0.0210) compared with AML with low BAALC expression; 53.7% of normal-karyotype AML had neither FLT3-ITD nor CEBPA mutations. We found that high BAALC expression in normal-karyotype AML with neither FLT3-ITD nor CEBPA mutations (18 of 67) indicates adverse prognosis for both DFS and OS (P = 0.0001; e.g., P = 0.0001) compared with the group with low BAALC expression and absent FLT3-ITD and CEBPA mutations (18 of 67). Thus, BAALC expression represents a novel prognostic marker particularly for normal-karyotype AML patients with neither FLT3-ITD nor CEBPA mutations. Assessment of CEBPA mutations, FLT3-ITD, and BAALC expression permits to split normal-karyotype AML into clinically distinct subgroups.