WT1, PRAME, and PR3 mRNA Expression in Acute Myeloid Leukemia (AML)

Abstract

Several tumor-associated antigens (TAAs) were recently identified, that could qualify as targets for immunotherapy, they could qualify (on RNA-level) for monitoring of tumor load. Here, we studied the expression levels of the immunogenic antigens PRAME (preferentially expressed antigen of melanoma), WT1 (Wilms’ tumor gene), and PR3 (proteinase 3) on myeloid blasts by real-time quantitative polymerase chain reaction and correlated these data to the state and course of disease and to the defined subgroups of acute myeloid leukemia (AML). At first diagnoses, 41 of 47 patients tested showed overexpression of PRAME (87%), 38 of WT1 (81%), and 26 of PR3 (55%), with the highest expression levels for PRAME (2048-fold), followed by WT1 (486-fold) and PR3 (196-fold). Thereby, with 70%, the most frequent combination at first diagnoses was detected to be PRAME and WT1 (33/47 patients). Overall, 21 patients (45%) revealed overexpression for all 3 TAAs. Moreover, the highest expression levels of PRAME were found to be correlated with the FAB subtype M5, cytogenetic unfavorable risk groups, and AMLs arising from myelodysplasia (secondary AML; P=0.02). To compare TAA expression levels in the course of disease, expression data were calculatory adjusted to 100% blasts, revealing a relative increase in the PRAME expression levels during the course of persistent disease (3/4 cases). Independent of stage of disease, by trend, higher TAA expression levels were found on blasts derived from peripheral blood than those derived from the bone marrow. In conclusion, it is suggested that vaccine strategies for cancer immunotherapy should comprise different TAA peptides anticipating the diverse TAA expression levels on blasts evolving during the course of disease or treatment.

Evaluation of CD30 expression in B ALL and its correlation with MRD(Minimum Residual Disease)

“…[ 8 ] Levels of MRD have a prognostic value in many hematologic malignancies. [ 9 10 11 12 13 14 15 ]…”

Trial Watch: Adoptive TCR-Engineered T-Cell Immunotherapy for Acute Myeloid Leukemia

“…PRAME is a repressor of the retinoic acid receptor [ 35 ]. Similar to WT1, PRAME is also overexpressed in different cancer types, including AML [ 36 ]. Approximately 30–87% of patients at diagnosis overexpress PRAME mRNA [ 36 , 37 , 38 ], and, as with WT1, it could be used as a surrogate marker of MRD in AML [ 37 ].…”

“…Similar to WT1, PRAME is also overexpressed in different cancer types, including AML [ 36 ]. Approximately 30–87% of patients at diagnosis overexpress PRAME mRNA [ 36 , 37 , 38 ], and, as with WT1, it could be used as a surrogate marker of MRD in AML [ 37 ]. Combined detection of WT1 and PRAME has been suggested to be a sensitive molecular biomarker for monitoring MRD in AML [ 39 ].…”

“…For some of these antigens, preclinical and clinical data hinted at their potential role as targets for TCR-T-cell therapy, including proteinase 3 (PR3), hyaluronan-mediated motility receptor (HMMR), and T-cell receptor γ chain alternate reading frame protein (TARP). Together with WT1 and PRAME, PR3 is an AML-associated antigen overexpressed in AML blasts [ 36 , 84 ]. These antigens are differentially expressed in leukemic stem cells (LSCs) compared to hematopoietic stem cells; however, PR3 diverged from the other antigens analyzed in that it was comparatively more expressed on bulk leukemic cells rather than LSC [ 85 ].…”

Dendritic Cells of Leukemic Origin: Specialized Antigen-Presenting Cells as Potential Treatment Tools for Patients with Myeloid Leukemia

“…Ex vivo DC can be generated from autologous or allogeneic CD14 + monocytes (monocyte-derived DC; mo-DC) [25]. Generated mo-DC have to be loaded with leukemia-associated antigens (LAA) which are overexpressed peptides or proteins on leukemic blasts compared to healthy tissue [26]. Wilms tumor antigen 1 (WT1), preferentially expressed antigen in melanoma (PRAME), and human telomerase reverse transcriptase (hTERT) are widely used LAA for the loading process of mo-DC [25, 27, 28].…”