PRAME-Induced Inhibition of Retinoic Acid Receptor Signaling-Mediated Differentiation—A Possible Target for ATRA Response in AML without t(15;17)

Abstract

Purpose: In acute myeloid leukemia (AML) without retinoic acid receptor (RAR) rearrangement, the effect of all-trans-retinoic acid (ATRA) is still poorly understood despite an association of NPM1 mutation and ATRA response. Recently, preferentially expressed antigen in melanoma (PRAME) has been shown to be a dominant repressor of RAR signaling.Experimental Design: Thus, we further investigated ATRA response mechanisms, especially the impact of PRAME expression on ATRA responsiveness. We profiled gene expression in diagnostic samples derived from our AML HD98B trial, in which ATRA was administered in addition to intensive chemotherapy.Results: Our data revealed a PRAME expression-associated gene pattern to be significantly enriched for genes involved in the retinoic acid metabolic process. In leukemia cell line models, we could show that retinoic acid-regulated cell proliferation and differentiation are impacted by PRAME expression. In patients with primary AML, repressor activity of high-PRAME levels might be overcome by the addition of ATRA as indicated by better outcome in 2 independent studies (P ¼ 0.029).Conclusions: PRAME seems to impair differentiation and to increase proliferation likely via blocking RAR signaling, which might be reversed by ATRA. PRAME therefore represents a promising target for both ATRA treatment and possibly future immunotherapeutic approaches in AML.

An ATRActive future for differentiation therapy in AML

“…MN1, another commonly overexpressed oncogene in AML, directly binds to RAR to inhibit retinoic acid signaling 35 . Bullinger et al have recently reported overexpression of PRAME1, a member of the RAR-associated co-repressor complex, in AML 36 : interestingly, high levels of PRAME were associated with ATRA responsiveness in the ULM AML 07-04 trial.…”

A therapeutic T cell receptor mimic antibody targets tumor-associated PRAME peptide/HLA-I antigens

“…Only minimal positive shifts in median fluorescence intensity (MFI) After the preliminary biochemical and specificity characterization, we sought to determine whether Pr20 could recognize cancer cells expressing endogenous PRAME protein. PRAME mRNA expression was assessed by quantitative PCR (qPCR), and surface HLA-A2 expression and Pr20 binding were assessed by flow cytometry across a panel of HLA-A2 + hematopoietic and solid tumor cell lines, several of which have been reported to express PRAME by other groups (10,12,16,30,31) (Table 1 and Figure 1C). Pr20 binding was readily detected in PRAME + HLA-A2 + leukemia AML14, SET2, BV173, and the T cell lymphoma MAC2A, demonstrating that Pr20 can detectably bind endogenously processed and presented peptides ( Figure 1D).…”

Clinical Significance of the PRAME Gene Expression in Oncohematological Diseases

“…Вероятно, это вызвано большей доступностью лейкозных клеток, циркулирующих в крови, для иммунной атаки. Однако при ОМЛ не наблюдается PRAME-опосредованного снижения уровня экспрессии гена TRAIL [71]. При этом результаты экспериментов с клеточными линиями не упрощают объяснение позитивного значения экспрессии PRAME при ОМЛ.…”

“…При этом результаты экспериментов с клеточными линиями не упрощают объяснение позитивного значения экспрессии PRAME при ОМЛ. Так, клетки линии KG1 после трансфекции (процесс введения нуклеиновой кислоты в клетки эукариот невирусным методом) геном PRAME медленнее росли, хуже формировали колонии, а интенсивность каспаза-3-независимого апоптоза в них увеличивалась [67,69,71]. В то же время клетки линий HL60 и NB4 после трансфекции геном PRAME повышали скорость пролиферации [9].…”

“…Однако негативный эффект, вызванный блоком дифферен-цировки, может быть нивелирован включением ATRA в протоколы лечения больных ОМЛ. Действительно, ATRA позволила добиться лучших результатов те-рапии в группе больных с гиперэкспрессией PRAME по сравнению с остальными [71].…”