AKR1C3 Expression May Hold Potential as a Biomarker, Clinical Target in T-ALL

Aldo-keto reductase 1C3 (AKR1C3) expression has been identified as a potential biomarker and therapeutic target in several cancer types, and a recent study published in Scientific Reports suggests it might be a useful marker for minimal residual disease (MRD) and therapy in patients with T acute lymphoblastic leukemia/lymphoma (T-ALL).

T-ALL and B acute lymphoblastic leukemia/lymphoma (B-ALL) are hematological cancers that have seen improved survival rates in recent years. T-ALL, however, has proven more difficult to treat effectively, with these patients more likely to be unresponsive to induction therapy or relapse early after initially responding.

Overexpression of AKR1C3 plays a role in cell proliferation and has been implicated in other cancer types, such as endometrial, breast, prostate, and non–hormonal dependent malignancies, such as acute myeloid leukemia (AML). The current a study aimed to clarify the potential role of AKR1C3 expression in monitoring and treating patients with residual or recurrent ALL.

Four cell line controls (Nalm6, HCT116, HCT116-AKR1C3, and TF1), peripheral blood and marrow samples from patients with T-ALL and B-ALL, and disease-free samples from patients with histories of AML, mantle cell lymphoma, and diffuse large B-cell lymphoma were used for the assays in the study. AKR1C3 expression levels were evaluated by immunohistochemistry (IHC), Protein Wes, and quantitative reverse transcription-polymerase chain reaction (RT-qPCR).

The study authors assessed 3 commercial antibodies for AKR1C3 IHC staining performance. The Sigma/Millipore anti-AKR1C3 antibody, mouse monoclonal, clone NP6.G6.A6, purified from hybridoma cell culture produced expected AKR1C3 expressions and was chosen for the study.

AKR1C3 IHC was optimized on cell lines with expression levels already confirmed by Protein Wes experiments, then the assay was applied to T-ALL bone marrow samples. The IHC assay showed a positive correlation between disease involvement and the samples’ H-scores, which were used to quantify the extent of nuclear immunoreactivity for AKR1C3 with varying disease blast involvements. In B-ALL, disease involvement correlated poorly with H-scores.

There was a statistically significant cutoff at 20% or greater blast involvement in this study. Therefore, this was set as the threshold for positivity and showed 100% sensitivity and 88.9% specificity for singleplex AKR1C3 IHC assay in T-ALL. All B-ALL samples in the cohort had 20% or greater blast involvement, so specificity could not be calculated in this group.

In patients with T-ALL with 20% or greater circulating blast involvement, RT-qPCR was found to be a suitable alternative approach if a liquid biopsy of peripheral blood is the only available sample. With RT-qPCR, peripheral blood was shown to be more sensitive than bone marrow testing, likely because normal bone marrow cells express AKR1C3. In peripheral blood, AKR1C3 expression during initial diagnosis, refractory/residual disease, and MRD specimens was consistently high.

Given the required 20% or greater blast percentage threshold, the study authors do not recommend using singleplex IHC or bone marrow RT-qPCR assays on T-ALL samples with MRD alone or with low levels of residual disease. However, the authors note that future studies of multiplexed IHC could lead to more sensitive IHC assays.

Overall, this study’s findings in tandem with those from previous studies suggest AKR1C3 expression correlates with disease involvement and potential response to therapy for patients with T-ALL.

“We have demonstrated 2 validated assays, both RT-qPCR and Protein Wes, which showed increased AKR1C3 expression in both peripheral blood and bone marrow aspirate of T-ALL specimens,” the authors concluded. “Future studies with a larger patient cohort will further validate the use of AKR1C3 in clinical settings. In addition, more studies in AKR1C3-targeted therapy will help improve cancer care in patients with T-ALL.”

Reference

Reddi D, Seaton BW, Woolston D, et al. AKR1C3 expression in T acute lymphoblastic leukemia/lymphoma for clinical use as a biomarker. Sci Rep. Published online April 6, 2022. doi:10.1038/s41598-022-09697-6